Jichi Medical Research Overview 2015

Division/Department:
Division of Anatomy, Bio-imaging and Neuro-cell Science

Theme of research:
Molecular mechanism of the morphological change of the living cell during cell
differentiation and migration.
Name of main researcher, title, and e-mail address:
Yasuko Noda, M.D. & Ph.D., Professor and chairman, ynoda@jichi.ac.jp
Brief explanation of research activity:

We are interested in the molecular mechanism of the dynamics of intracellular organelles
and effects on the morphology of the cell. We conduct real-time observation of
membrane-associated molecules involving intracellular organelles and cytoskeletal
proteins, using double, triple, or quadruple fluorescent labeling in live cell imaging. We
analyze dynamics in living cultured cells with a high-resolution deconvolution
fluorescence microscopy system.
Division of Histology and Cell Biology, Department of Anatomy
Theme of research:
Cellular, Structural and Functional Biology of the Organ
Takashi Yashiro, MD and PhD, Professor, tyashiro@jichi.ac.jp
Ken Fujiwara. PhD, Assistant Professor, ken_fuji@jichi.ac.jp
Takehiro Tsukada. PhD, Research Professor, tsukada@jichi.ac.jp
Morio Azuma. PhD, Research Professor, azumam@jichi.ac.jp
Various sorts of cells are harmonized to provide integrated responses of the tissue in
organism. This coordination cannot be achieved without cells recognize specific
microenvironment they have laid, through cues issued from cell-cell and cell-matrix
adhesion. Our interests base on a question how functions of endocrine cells are modified
by the microenviromental cues, in addition the humoral and neural controls, especially for
the anterior pituitary cells. This microenvironment might play important roles on the
cell differentiation from the stem cell, tumor genesis and regeneration of the organ or
tissue.
In the pituitary gland, we are clarifying mechanism that makes the specific cell
attachment, and functional role of the specific cell attachment by studying : 1) cell
adhesion molecules using techniques including immunohistochemistry, in situ
hybridization and immunoelectron microscopy, as well as possible outside-in signal
transduction by the molecules, 2) cell type specific sugar chain expression on cell
membrane, 3) metricrine modulation of hormone-producing cells raised by
cell-extracellular matrix adhesion, 4) cell communications through gap junctions and 4)
juxtacrine modulation of hormone gene expression by specific cell attachment, utilizing a
technique of reporter gene transfection which enables us to observe gene expression in
live cells.
Division of Forensic Medicine, Department of Anatomy
Theme of research:
Study on fluorescent granular perithelial(FGP)cell.
Prof. Atsushi Sakamoto ,legalmed@jichi.ac.jp

FGP cells containing auto-fluorescent granules are reported to be located between blood
vessels and neural tissue in cerebral cortex by Mato et.al. The FGP cells are expected to
play an important role on the blood brain barrier(BBB), because these cells phagocyte
blood-born HRP as well as scavenge wastes/foreign substance in the brain tissue and also
show the presence of macrophage lineage receptors such as MHC-, which suggests an
immunological function of FGP cells in the BBB. So we are studying the further
distribution and function of FGP cells in the central nervous system.
Division of Biophysics, Department of Physiology
Theme of research:
Study on mechanisms of protein allostery
Naoya Shibayama, Professor, shibayam@jichi.ac.jp
Allostery, the process by which proteins change their shape upon binding small molecules
or ions, is used in many biological processes. Despite its importance, mechanisms of
allostery are still poorly understood. The hemoglobin molecule offers the best
experimental system for the study of mechanisms of allostery. To investigate the
molecular events that occur in hemoglobin, we have used a variety of approaches
including X-ray crystallography, neutron crystallography, various spectroscopic
techniques, site-directed metal-substitution, chemical cross-linking, sol-gel entrapment
(to lock in the hemoglobin conformation during measurement) and functional analysis
both in solution in crystals.
Division of Brain and Neurophysiology, Department of Physiology
Theme of research:
Neural mechanisms of stress, emotion and social behaviour
Yuki Takayanagi, Lecturer, t-yuki@jichi.ac.jp
Masahide Yoshida, Assistant Professor, y-masa@jichi.ac.jp
Tatsushi Onaka, Professor, tonaka@jichi.ac.jp
Stress, obesity, and social relationship largely affect clinical course of various diseases. However,
neural mechanisms of these factors remain unclear. Both genetic and environmental factors affect
stress responses, emotion-related behaviour or social behaviour. We have been investigating
neural mechanisms of stress, emotion or social behaviour by using various kinds of methods
including molecular genetics.
Current research topics:
1) Neural and molecular mechanisms of social behaviour
2) Neural and molecular mechanisms of acute or chronic stress
3) Neural and molecular mechanisms of interactions among stress, energy metabolisms and
social behaviour
4) Neural and molecular mechanisms of endogenous anti-stress, anti-obesity and pro-social
systems
References
Science 34:333-336, 2015.
Endocrinology 155:2996-3004, 2014.
J Neuroendocrinol 25: 455-465, 2013.
Nature 464: 413-417, 2010.
Trends Endocrin Met 21: 287-293, 2010.
J Neurosci 29: 2259-2271, 2009.
J Clin Invest 118: 40144024, 2008.
Division of Brain and Neurophysiology, Department of Physiology
Theme of research:
Physiological functions of vasopressin and oxytocin in the central nervous system
Masahide Yoshida, Assistant Professor, y-masa@jichi.ac.jp
Yuki Takayanagi, Lecturer, t-yuki@jichi.ac.jp
Tatsushi Onaka, Professor, tonaka@jichi.ac.jp
Vasopressin and oxytocin are synthesized mainly in the hypothalamic neurons and released not
only from their axonal terminals but also from dendrites or cell bodies in the hypothalamus.
Central administration of vasopressin or oxytocin affects emotional or social behaviour. Receptors
for vasopressin or oxytocin are distributed in the brain. Vasopressin or oxytocin receptor-deficient
mice show abnormal emotional or social behavior. However, neural and molecular mechanisms of
the actions by vasopressin or oxytocin remain unclear.
Current research topics:
1) Physiological roles of vasopressin or oxytocin within the hypothalamus
2) Neural and molecular mechanisms of developmental actions by vasopressin or oxytocin
3) Neural and molecular mechanisms of dendritic vasopressin or oxytocin release
References
Endocrinology 155:2996-3004, 2014.
Nature 464: 413-417, 2010.
J Neurosci 29: 2259-2271, 2009.
Horm Behav 55: 434-441, 2009.
J Clin Invest 118: 40144024, 2008.
Proc Natl Acad Sci USA 102: 16096-16101, 2005.
Department/Division:
Physiology/Integrative physiology
Theme of research:
Ghrelin regulates insulin release and blood glucose level: physiological significance and
therapeutic potential
Katsuya Dezaki, Tomoyuki Kurashina, Masanobu Taguchi, Rauza S. Rita, Masanori
Nakata, Toshihiko Yada
Principal Investigator:
Katsuya Dezaki, Associate Professor, dezaki@jichi.ac.jp
Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor
(GHS-R), is produced predominantly in the stomach and potently stimulates GH release
and feeding. Our studies have established ghrelin as a novel islet hormone that inhibits
insulin release and thereby upwardly regulates blood glucose, which was evidenced by the
following findings.
Ghrelin and GHS-R are expressed in pancreatic islets [1,2], and ghrelin is released into
the pancreatic vein [3]. Ghrelin immunoneutralization and GHS-R antagonists augment
glucose-stimulated insulin secretion (GSIS) from isolated pancreas and islets [2]. GHS-R
blockade increases plasma insulin concentration in gastrectomized and normal rats
similarly [3]. Ghrelin acts on islet -cells and attenuates glucose-induced cAMP
production, which drives activation of voltage-dependent Kv channels and suppression of
the glucose-induced [Ca2+]i increases and insulin release [4,5]. GSIS is greater in
ghrelin-deficient than wild-type mice [3]. Thus, pharmacological, immunological and
genetic blockade of ghrelin or ghrelin action in pancreatic islets all markedly enhance
GSIS. Moreover, ghrelin deficiency enhances insulin release and prevents the high-fat
diet-induced impaired glucose tolerance [3]. Ghrelin also attenuates glucagon-like
peptide-1 (GLP-1)-potentiated insulin release by suppression of cAMP production in
-cells [6]. Low doses of GLP-1 agonist and Kv2.1 channel blocker synergistically
stimulate insulin release and lower blood glucose in type 2 diabetic mice [7].
Thus, ghrelin inhibits glucose-induced and GLP-1-potentiated insulin release, and
manipulation of insulinostatic function of ghrelin in islets could optimize insulin release to
meet the systemic demand, providing a novel therapeutic tool to treat type 2 diabetes
[8,9]. We aim to fully elucidate the action mechanisms of ghrelin, and to develop a novel
ghrelin-based treatment for type 2 diabetes and possibly metabolic syndrome.
Surgery is the main therapy in the patients with gastric cancer, but postoperative
dysfunctions such as impaired food intake and weight loss lead to a difficulty in recovery
of the quality of life. We aim to elucidate the mechanism of postoperative dysfunctions,
and to evaluate its intervention using Kampo medicine.
[1] Diabetes 51:124-129, 2002, [2] Diabetes 53:3142-3151, 2004, [3] Diabetes
55:3486-3493, 2006, [4] Diabetes 56:2319-2327, 2007, [5] Diabetes 60:2315-2324, 2011,
[6] FEBS Lett 586:2555-2562, 2012, [7] Endocrinology 156:114-123, 2015, [8] Methods
Enzymol 514:317-331, 2012, [9] Diabetes Obes Metab 1:111-117, 2014
Theme of research:
The hypothalamic and vagal afferent neurons senses systemic signals to regulate feeding
and bodys functions
Yusaku Iwasaki, Shigetomo Suyama, Parmila Kumari, Masanori Nakata, Katsuya
Dezaki, Kenichi Katsurada, Eisuke Takano, Toshihiko Yada
Toshihiko Yada, Professor, tyada@jichi.ac.jp
The hypothalamus receives peripheral metabolic signals that enter the brain through the
blood-brain barrier (BBB), and regulates feeding behavior and energy metabolism. The orexigenic
neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC), the first order center,
are directly activated by low glucose [1], ghrelin [2], orexin [3] and PACAP [4], while inhibited by
leptin [5], insulin [6] and GABA [7]. NPY neurons integrate these orexigenic and anorexigenic
signals: leptin counteracts the ghrelin-induced stimulation of NPY neurons and feeding [5]. Type 2
diabetic GK rats display hyperphagia and visceral obesity due to leptin resistance and dysfunction
of ARC NPY neurons [8]. We now aim to elucidate the neural circuit that relays the ARC to the
paraventricular nucleus (PVN), the second order center, and to feeding behavior. Nesfatin-1 [9],
BDNF [10] and GLP-1 [11] in the PVN play a key role in suppressing food intake.
The vagal afferent nerves sense the peripheral information and convey these signals to the
brain, resulting in regulation of feeding and metabolism. We established a new method of
analyzing the vagal afferent nodose ganglion neuron (NGN). Cytosolic Ca2+ concentrations and
membrane currents in single NGNs isolated from rodents are measured by fluorescence imaging
and patch clamp technique, followed by immunocytochemical identification of their
neurotransmitters. We have found that the vagal afferent NGNs directly sense
gastrointestinal/pancreatic hormones, GLP-1 [12], nesfatin-1 [13], peptide YY3-36 [14], insulin
[15], glucagon [16] and pancreatic polypeptide [14], thereby conveying the signals to the brain to
regulate feeding. Recently, we have found that peripheral administration of oxytocin reduces
feeding and ameliorates obesity via direct interaction with vagal afferents [17,18]. We are studying
the role of the vagal afferent-mediated peripheral-central network in physiological regulation of
feeding, metabolism and brain functions. Dysfunction of the vagal afferents may be implicated in
the metabolic and neural diseases including feeding disorders, obesity, diabetes, blood pressure,
depression and Alzheimer disease.
[1] Neurosci Lett 264:113-6, 1999, [2] Diabetes 52:948-56, 2003, [3] Eur J Neurosci 19,1524-34,
2004, [4] Neruosci Lett 370:252-6, 2004, [5] Endocrinology 148; 2251-63, 2007, [6] Aging
3(11):1092-7, 2011, [7] Neuroreport 16:897-901, 2005, [9] Cell Metabolism 10: 355-65, 2009,
[10] J Neuroendocrinology, 22(9):987-95, 2010, [11] BBRC 451(2):276-81, 2014, [8] J
Neuroendocrinol 18:748-756, 2006, [12] Auton Neurosci 102:39-44, 2002, [13] BBRC
390:958-962, 2009, [14] Neuropeptides 47:19-23, 2013, [15] PLOS ONE 8(6):e67198, [16] BBRC
456(3):727-32, 2015, [17] Aging 3(12):1169-77, 2011, [18] Am J Physiol Regul Integr Comp
Physiol 308(5):R360-9, 2015
Theme of research:
Network and therapeutic potential of nesfatin-1 and oxytocin to treat obesity syndrome
and psychiatric disorders
Toshihiko Yada, Putra Santoso, Yifei Yang, Zesemdorj Otgon-Uul, Parmila Kumari,
Kenichi Katsurada, Yusaku Iwasaki, Katuya Dezaki, Masanori Nakata
Yuko Maejima, Assistant professor, maejimay@jichi.ac.jp
To develop an effective treatment of obesity and metabolic syndrome, it is essential to
clarify the regulation of feeding and energy metabolism. We discovered a novel
neuro-circuit operated by new and clasic neuropeptides, nesfatin-1 (Nesf) and oxytocin
(Oxt), in the hypothalamic paraventricular nucleus (PVN). The PVN Nesf neurons induce
oxytocinergic signaling to proopiomelanocortin (POMC) neurons located in the arcuate
nucleus (ARC) [1] and in the brain stem nucleus tractus solitarius (NTS) [2]. The PVN
Nesf is regulated by leptin and mediates the anorexigenicic effect of leptin [3]. Nesf in
PVN is activated by meal [4], the neural projection from the ARC [5], and glucose and
insulin [6]. Nesf neurons are also activated by stressors and in turn provoke
CRH-ACTH-glucocorticoid and serotonin pathways, the stress/psychiatric systems [7].
Furthermore, the PVN Nesf/NUCB2 mRNA expression is raised in light phase (LP),
which is tightly linked to feeding suppression at LP. We have demonstrated that diurnal
Nesf/NUCB2 rhythm drives circadian feeding rhythm [8].
Nesf is also localized in the peripheral tissues and in the circulation. We found that
both Nesf and Oxt, when injected peripherally, also inhibit feeding [9,10]. Peripheral Oxt
treatment corrects obesity and metabolic syndrome [10]. These effects of peripheral Oxt is
largely mediated by its direct activation of the vagal afferent nerve and resultant signaling
to the brain [11]. Nasal and IP administrations of Oxt similarly inhibit feeding [12]. Our
goal is to clarify (patho)physiological roles of Nesf and Oxt in the regulation of feeding
and psychiatric behaviors, and to invent an Oxt-based effective and safe treatment of
obesity.
[1] FEBS Letters 588:4404-4412, 2014, [2] Cell Metabolism 10:355-365, 2009, [3]
Biochem Biophys Res Commun 456:913-918, 2015, [5] Endocrinology 149:1295-1301,
2008, [5] NeuroReport 25:1453-1458, 2014, [6] Biochem Biophys Res Commun
420:811-815, 2012, [7] Aging 2:775-784, 2010, [8] Biochem Biophys Res Commun
434:434-438, 2013, [9] Endocrinology 150:662-671, 2009, [10] Aging 3:1169-1177, 2011,
[11] Am J Physiol 308:R360-R369, 2015, [12] Neuroendocrinology 101:35-44, 2015.
Physiology / Integrative Physiology
Theme of research:
Elucidating the mechanisms of circadian rhythms of feeding and metabolism
Masanori Nakata, Rai Wang, Yifei Yang, Toshihiko Yada
Masanori Nakata, associate professor, nakata@jichi.ac.jp
The circadian system in mammals is organized by a network of circadian oscillators.
The master clock is located in the hypothalamic suprachiasmatic nucleus (SCN), in which
approximately 20,000 neurons are synchronized in their activities. Partly under the
influence and partly independently of the SCN master clock, circadian oscillators are
present in other brain areas and peripheral organs, which are thought to be implicated in
the circadian rhythms of physiological functions, including the rhythms of feeding and
hormone release.
We intend to demonstrate that the impairment of circadian rhythms induced by
environment factors induces feeding disorder, metabolic syndrome and depression, and to
elucidate the underlying mechanisms.
PVN is considered a regulatory center for feeding and circadian activities of hormone
release and autonomic nerve. Nucleobindin2 (NUCB2) and its processing product
nesfatin-1 (NUCB2/nesfatin-1) are localized in the hypothalamic paraventricular nucleus
(PVN) and implicated in regulation of feeding. We reported that NUCB2 mRNA
expression in the PVN rises during early light phase (LP) in parallel with suppression of
food intake [1]. Furthermore, the rise of PVN NUCB2 mRNA during LP was blunted in
obese rats which exhibited LP-preferential hyperphagia. These results suggested that the
circadian rhythm of PVN NUCB2 mRNA expression regulates circadian pattern of
feeding. In addition, the function of nesfatin-1/NUCB2 neuron in PVN is regulated by
meal-induced factors such as high glucose, insulin and leptin [2,3]. Nesaftin-1/NUCB2
may play a role in coupling energy metabolism and circadian rhythms. Using PVN
specific conditional NUCB2 knockout mice and knockdown mice expressing NUCB2
shRNA by AAV vector, we aim to further explore the function of NUCB2.
[1] Sedbazar U et al. Biochem Biophys Res Commun. 434:434-438, 2013.
[2] Gantulga D et al. Biochem Biophys Res Commun. 420:811-815, 2012.
[3] Gantulga D et al. Biochem Biophys Res Commun. 456:913-918, 2014
Division of Structural Biochemistry, Department of Biochemistry
Theme of research:
Studies on biosynthesis of selenocysteine, selenoproteins and the related molecules
Jitsuhiro Matsugi, Associate Professor, jmatsugi@jichi.ac.jp

In many cases, selenoproteins function as redox protein like glutathione
peroxidases and thioredoxin reductases and they contain selenocysteine (Sec) in the
catalytic center. Thus, it is thought that selenoproteins are strongly associated with
tumorigenesis, aging and other stress-related phenomena. For biosynthesize
selenoproteins, specific mechanisms are employed in its translational system, such as
its assigned codon, unique tRNA, elongation factor and cis-element in the mRNA.
Since it has been confirmed that selenoproteins are essential for higher animals, Sec
is referred to the 21th amino acid. In my research, the structural feature of the
molecules necessary for biosynthesis of selenoprotein is investigated using
biochemical techniques.
Theme of research:
Molecular mechanism of high-fidelity chromosome transmission
Satoshi Ohta, Ph.D., Research Associate, Satoshi.ohta@jichi.ac.jp

My general interests involve understanding the regulation of cellular growth control. The aim is to
understand how a tumorigenic cell growth differs from a normal one. My research focuses on the
role of NF-HEV/IL-33 in cell growth and oncogenic signaling pathway. Although
NF-HEV/IL-33 is reported to be localized in nucleus, currently, the nuclear function of
IL-33 is not well understood. In addition, I have been involved in a collaboration
searching for novel tumor makers from colorectal cancer patients.
Theme of research:
Signaling crosstalk of proto-oncogenes products and tumor suppressors
Kenji Tago, Ph.D., Assistant Prof., ktago@jichi.ac.jp

Disruption/silencing of tumor suppressing signals and/or hyper-activation of cell
proliferative signals are known to be the triggers for tumorigenesis. We are focusing
on the signaling crosstalk between proto-oncogenes products including Ras and Myc,
and tumor suppressor Arf and p53. We identified an RNA helicase DDX5 as a novel
interacting protein of Arf tumor suppressor, and found that Arf suppresses the
function of DDX5 and this seems to be a mechanism of Arf-induced tumor suppressive
signals. We are also interested in the function of novel nuclear-cytosolic small GTPase
NKi-Ras. Our current observations suggest that NKi-Ras seems to harbor the
critical roles in tumorigenesis. We recently identified several interacting proteins of
NKi-Ras, and now attempt to clarify their functions.
Division of Functional Biochemistry, Department of Biochemistry
Theme of research:
Comprehensive proteomic analysis of mammalian mitochondrial membrane proteins
Hitoshi Endo, Professor, hendo@jichi.ac.jp
Katsumi Kasashima, Assistant Professor, kasa@jichi.ac.jp
Kenji Kuroiwa, Assistant Professor, kkuroiwa@jichi.ac.jp
Mitochondria is an eukaryotic organelle that plays crucial roles in several cellular
process, including ATP production, fatty acid oxidation, apoptosis, calcium homeostasis
and reactive oxygen species (ROS) signaling and is closely related to human diseases,
such as metabolic syndrome, neuromuscular disease and aging. Although the number of
mammalian mitochondrial protein is predicted to be about 2,000, they are not totally
distinguished.
To understand the molecular mechanisms of mitochondrial functions, we performed a
comprehensive proteomic analysis focusing on mitochondrial membrane that provides a
space for most of important mitochondrial functions described above. To date, we have
identified 171 proteins from purified mitochondrial membrane fraction of HeLa cells by
2D-electrophoresis and LC-MS/MS. Among them, we selected 13 novel proteins, which
have no previous information about the function and localization. Eight proteins were
subcloned and confirmed to localize to mitochondria.We are now investigating precise
functions of the newly identified mitochondrial membrane proteins by biochemical and
molecular biological approaches.
Theme of research:
Function analysis of mitochondrial protein, PHBs
Kenji Kuroiwa, Assistant Professor, kkuroiwa@jichi.ac.jp
Prohibitins (PHBs), including PHB1 and PHB2, are evolutionally conserved and have
pleiotropic cellular functions, such as apoptosis, regulation of cell cycle, signal
transduction, and aging. PHB2 is known to act as transcriptional repressor in nucleus.
We identified PHB2s mitochondrial functions in anti-apoptosis and mitochondrial
morphology for the first time (Kasashima et al, 2006), and also observed that PHB2
shuttles between mitochondria and nucleus.
Showing that PHBs function differently in both organelles, and it is suggested that PHBs
mediate nuclear-mitochondrial interaction.
We are now investigating the novel PHBs functions in mitochondria and the relation
with the functions in nucleus.
Theme of research:
RNA processing and gene expression
Eiji Sakashita, Assistant Professor, esaka@jichi.ac.jp
Kaoru Tominaga, Associate Professor, tominaga@jichi.ac.jp

Our laboratory studies the mechanisms of gene expression at the posttranscriptional
level. One is the molecular details of how tissue-specific alternative splicing, i.e.,
inclusion or skipping of a variably spliced exon, occurs in mammalian cells. To
investigate the mechanism of alternative splicing, we work on human mitochondrial ATP
synthase gamma subunit gene (F1 gamma) whose alternative exon 9 is excluded only in
heart and skeletal muscle as a tissue-specific model substrate. We also investigate
intracellular movements of splicing factors including a subset of SR protein family, in
response to UV- and heat shock-induced stress signals. Another area is to investigate the
cellular role of developmentally-regulated RNA-binding protein (Drb1), newly cloned in
our laboratory. Drb1 gene is specifically expressed in fetal rat brain and gradually
reduced during development. Our current goals are (i) to identify RNA target(s); (ii) to
understand the mechanism of regulation; (iii) to make Drb1 knockout mice and check
the phenotype.
Theme of research:
Chromatin regulation for cell growth control and DNA damage repair
Kaoru Tominaga, Associate Professor, tominaga@jichi.ac.jp
Chromatin is composed of units of DNA and histone proteins and maintains the proper
three-dimensional structure of DNA. Chromatin structure needs to be modulated in many
cellular processes such as transcription, DNA replication, and DNA repair and proper
control of chromatin structure is critical for regulation of cellular activities. Chromatin
binding protein MRG15 was originally isolated through the studies of cellular senescence.
It has been shown that MRG15 regulates chromatin through making complexes with
histone acetyltransferases (HATs) and histone deacetylases (HDACs). Our studies using
Mrg15 knockout mice show that MRG15 is important for cell growth control including
neural stem cells (NSCs) and for DNA damage repair. We are currently investigating the
molecular mechanism(s) of MRG15 action in these cellular processes using Mrg15
deficient mouse embryonic fibroblasts (MEFs) and NSCs. Our studies should help to
increase our knowledge about the importance of chromatin modification and epigenetic
regulation as well as the molecular mechanism of diseases caused by dysregulation of
chromatin such as cancer and neurological disorders.
Division of Medical Biochemistry/Department of Biochemistry
Theme of research:
Development of next generation gene therapy by genome editing
Pathophysiological roles of forkhead box transcriptional factor
Tsukasa Ohmori MD,PhD,Associate Professor, E-mail: tohmori@jichi.ac.jp
1) The current types of gene therapy for an inherited disorder mainly utilize techniques to
ectopically express a normal gene by a vector, while leaving the abnormal somatic gene as it
is. An ideal gene therapy would repair the abnormal gene at the genomic DNA level. As
genome-editing technologies such as CRISPR/Cas9 systems have been significantly
improved, future applications of these technologies are anticipated. We are going to establish
technologies to treat patient genetic abnormalities by removing the abnormal gene and
replacing it with a normal gene, as a next generation treatment for inherited disorders
including hemophilia and severe immunodeficiency.
2) Forkhead box(FOX) proteins are a family of transcriptional factors to regulate cell growth
and differentiation. We identified a FOX protein as a downstream target of the cytoskeletal
protein Vinculin in hematopoietic stem cells by microarray analysis. We generated
conditional gene-deficient mice, and are now investigating the (patho)physiological roles of
the FOX protein in lung, heart, and blood cells.
Division of Bacteriology, Department of Infection and Immunity
Theme of research:
Pathogenicity and antibiotic resistance of clinical bacteria; Development of novel
antibacterial agents targeting H. Pylori; Infection control science
Longzhu Cui, Professor, longzhu@jichi.ac.jp
1) Pathogenicity and antibiotic resistance of staphylococcal species
a) We recently reported a prolonged persistent staphylococcal infection, the worst
case of staphylococcal infections, was due to the infection by a strain that
repeatedly reverts its half genome (Flip-Flop inversion), which switches bacterial
phenotype and generate heterogeneous cell population (Cui et al. PNAS 2012
p9686). Currently, we are expanding this finding into revealing the nature of
heterogeneity, one of the longest standing mysteries in bacterial physiology.
b) Our research on the antibiotic resistance of Staphylococcal species focuses on
uncovering mechanism of resistance against vancomycin, teicoplanin, linezolid
and daptomycin, and for the highly methicillin-resistant MRSA.
2) We also research on antibiotic resistance of opportunistic pathogens including K.
pneumoniae, P. aeruginosa and A. baumannii.
3) Development of novel antibacterial agents
We previously found out some novel compounds that have species-specific
bactericidal activity against Helicobacter pylori. We are now evaluating these
compounds toward drug development.
4) Infection control science
In collaboration with infection control team, our group manages infection control in
university teaching hospital by combining basic research and laboratory
surveillance.
Division of Virology, Department of Infection and Immunity
Theme of research:
Molecular epidemiological and molecular biological studies on hepatitis viruses
Hiroaki Okamoto, Professor, hokamoto@jichi.ac.jp
Masaharu Takahashi, Assistant Professor, mtaka84@jichi.ac.jp
Shigeo Nagashima, Assistant Professor, shigeon@jichi.ac.jp
Tominari Kobayashi, Research Assistant, tominari-tm@jichi.ac.jp
Our research projects, now in progress, are as follows:
1. Studies on genomic organization, genomic mutation and pathogenesis of hepatitis
viruses including HAV, HBV, HCV, HDV, and HEV as well as Torque teno viruses and
related viruses
2. Studies on viral replication using cell culture systems
3. Development of methods for serological diagnosis of acute and chronic liver diseases
4. Development of methods for genomic diagnosis of acute and chronic liver diseases
5. Phylogenetic analyses and development of methods for genotyping of various hepatitis
viruses
6. Molecular epidemiological studies on hepatitis virus infections for elucidating
infectious sources and transmission routes and for developing preventive measures
7. Investigation of the prevalence of hepatitis virus infections among various populations
in Asian countries including Mongolia, China, Nepal, Vietnam, the Philippines, and
Indonesia.
8. Identification and characterization of novel viruses related to diseases of unknown
etiology
Details of our research activities are available at
http://www.researcherid.com/rid/H-4371-2011.
Division of Medical Zoology
Theme of research:
1. Malaria epidemiology and vector control
2. Transgenic mosquito
3. Transgenic malaria parasite
4. Development of malaria vaccine
1. Hiroyuki Matsuoka Professor hiroyuki@jichi.ac.jp
2. Daisuke Yamamoto Assistant Professor daisukey@jichi.ac.jp
1-1. Malaria epidemiology
We have developed simple techniques for malaria diagnosis and G6PD activity test.
These can be used in rural areas, where no water and no electricity are available. We are
visiting malaria endemic areas in Asian and African countries to demonstrate these
methods.
1-2. Vector control in tropical areas
To reduce vector mosquitoes in tropical countries, we are testing the efficacy of copper
solution. Because copper can give damage to mosquito larvae in very low concentrations.
2. Transgenic mosquitoes
To reduce malaria transmit ability of Anopheline mosquitoes, we are adding some
genes in Anopheles stephensi (Jichi Med Univ) and A. gambiae (Noguchi Institute,
Ghana).
3. Transgenic malaria parasites
To observe the movement of malaria parasite (Plasmodium berghei), we have
introduced GFP gene or luciferase gene in the parasite. We are now able to follow the
movement of malaria parasite in the skin, in the blood and in the mosquito organs.
4. Development of malaria vaccine
For malaria vaccine development, we focus on its cytotoxic T lymphocytes: the
essential factor for anti-malaria immunity. Through analysis of activated / expanded
cytotoxic T lymphocytes by attenuated malaria sporozoite immunization, we try to find
the essential malaria antigens for anti-malaria immunity.
Division of Clinical Infectious Diseases, Department of Infection and Immunity
Theme of research:
Healthcare-associated Infection Prevention and Control, including Environmental
Bacteriology, Occupational Safety and Health for Healthcare Providers, and
Antimicrobial Stewardship
Yuji Morisawa, MD, Associate Professor, yujim@jichi.ac.jp
The Division has been established since 2004, to promote patient safety and healthcare
personnel safety. With the Jichi Medical University Hospital and affiliated hospitals in
Tochigi region as research fields, we are focusing on the prevention and control of
healthcare-associated infections. We have reported the Bacillus cereus outbreak
originated from highly contaminated hospital linens, to make nation-wide regulations
anew.
Antimicrobial stewardship is another concern. We would like to innovate an original
program to train infectious diseases specialists fit in real Japan.
Department of Pharmacology, Division of Molecular Pharmacology
Theme of research:
Molecular pharmacology of G-protein coupled hormone receptors as drug targets.
Taka-aki Koshimizu, Associate professor, t_koshi@jichi.ac.jp
Our laboratory focuses on the study of G-protein-coupled receptors to develop novel
drug therapy. By using chemical tools specifically designed for this receptor family, we
are trying to understand underling mechanism for a variety of pharmacological responses
occurring in different biological systems, from cells to organs and to whole bodies.
Among the different biological responses caused by a drug treatment, we can now look
into transcriptome, proteome and transcription factor binding sites in a genome-wide
scale, to find a new therapeutic target or marker molecule. Delineating mechanism of drug
side effects is another important topic in our laboratory. Students in our group will learn
how to design and perform pharmacological experiment, analyze own data by integrating
large public database, and publish their work in a scientific journal.
Division of Clinical Pharmacology, Department of Pharmacology
Theme of research:
Toxicogenomics
Akio Fujimura, Professor, akiofuji@jichi.ac.jp

To clarify the mechanisms of drug toxicity and develop safer agents, effects of various
medications on gene expression are analyzed in genome-wide basis using the gene chips.
We have found useful biomarkers indicating potential renal toxicity of agents in human.
Division of Clinical Pharmacology, Department of Pharmacology
Theme of research:
Chronopharmacology and Chronotherapy
Akio Fujimura, Professor, akiofuji@jichi.ac.jp

A number of physiological functions such as central neuron activity,
hormone secretion and blood pressure show daily rhythms. In addition, the
expressions of many enzymes involved in xenobiotic detoxification
(cytochrome P450 enzymes and drug transporters) are also changed during a
24-hour period.
Because of these daily rhythms, pharmacokinetics and/or pharmacodynamics
of drugs are altered by its dosing-time.
Chronopharmacolgy/Chronotherapy is one of the approaches to increase the
effects of drugs and to decrease their adverse effects by optimizing the
dosing-time.
Department of Environmental and Preventive Medicine
Theme of research:
Developmental immunotoxicology by endocrine disrupting chemicals
Fujio Kayama, M.D., Ph.D., Professor, kayamaf@jichi.ac.jp
Growing fetus and neonates are very vulnerable to the environmental factors. Chemicals
such as arsenic, lead and lipid-soluble persistent organic pollutants such as DDT and
PCBs are easily transferred into the growing fetus through placenta.
Blood-placenta barrier does not function well enough for these man-made chemicals.
Endocrine disruptors such as DDT, and PCBs are used as a model chemical to examine
the effects on developing immune systems in fetus and neonates of mice and rats. In this
projects, we will study adverse effects of chemicals on immune functions and host
resistance such as efficacy of vaccination, and antibody production.
Department of Environmental and Preventive Medicine
Theme of research:
National Birth Cohort Study in chemical exposure

Fujio Kayama, M.D., Ph.D., Professor, kayamaf@jichi.ac.jp

Fetus and infants has exposed to many kinds of chemicals in their early life. Specially, it is
well-known that a certain chemical has a narrow window to affect fetal development and
eventually the outcome will be surfaced in the later days in their juvenile period
or adulthood. To answer these difficult questions, we started the National Birth Cohort
Study sponsored by Ministry of Environment, Japan. We also started an epidemiological
study of pregnant women in Pakistan, who exposed to arsenic (As) by drinking the well
water. As a graduate student, you can study the topics and use our existing data set to be
analyzed and publish papers as well as helping organizing the projects.
Division of human Pathology, Department of Pathology
Theme of research:
Sex hormones and cell growth.
Akira Tanaka MD,PhD.
Using androgen-dependent mouse mammary SC-3 cells, we have found that
androgen-induced expression of FGF8 is essential for the androgen-dependent growth of
SC-3 cells. In addition, we have also found that FGF8 is frequently expressed in human
prostate and breast cancers. We are now under investigation on the subjects described
below:
Molecular mechanism of the FGF8 gene regulation by androgen.
Molecular mechanism of acquisition of androgen insensitivity after androgen
withdrawal.
Investigation on non-generic signaling pathways stimulated by androgen in SC-3 cells.
Division of Integrative Pathology, Department of Pathology
Theme of research:
Molecular Targeted Therapy of Cancer, Epigenetics, microRNA and Cancer,
Cancer-stromal interaction, Tumor Microenvironment
Toshiro NIKI, Professor;
Daisuke Matsubara, Associate Professor;
Taichiro Yoshimoto, Assistant Professor;
We have been interested in identification of new molecular targets in carcinomas of the
lung and gastrointestinal organs. One line of research ongoing in our lab focuses on
cancer-stromal interaction and microenvironment; both of these topics are currently
investigated using in vitro 3-dimensional culture and xenograft models. Another line of
research focuses on epigenetics and recently described class of small regulatory RNAs
known as microRNAs (miRNAs). Accumulating evidence demonstrates that miRNAs
play key roles in normal physiology and are commonly dysregulated in various human
diseases. We are trying to understand how aberrant miRNA activity contributes to
disease states such as cancer. Epigenetics involves changes in DNA and chromatin
structure, such as genomic imprinting, DNA methylation, and histone modification,
and these epigenetic changes are remembered by the cells when they divide. Projects
are now underway to elucidate the epigenetic alterations that underlie the differences
between cancer and normal cells.
Division of Cardiovascular Medicine, Department of Medicine
Theme of research:
Development of new technologies in blood pressure monitoring, and clinical study projects on morning
and nocturnal hypertension.

Kazuomi Kario, MD, FACP, FACC, F AHA, FESC, Professor, kkario@jichi.ac.jp

Our department has organized the following ongoing projects for clinical research.
1)Development of new technologies in the blood pressure monitoring
We have developed IT monitoring for management of hypertension. In particular, when the east-Japan
earthquake occurred, we set up and utilized this system (the Disaster Cardiovascular Prevention
Network [D-CAP]). DCAP is a system which installs a sphygmomanometer with a
communication function in a shelter, and transmits the measured blood-pressure value to a
computer server. And it is possible to specify higher-risk patients in inputting a DCAP risk
score and prevention score into a system. By now, the Great East Japan Earthquake evacuees
from Minami Sanriku-cho area have been able to leave the shelter. In order to continue taking
measurements, they were given individual blood pressure monitor systems. We would like to
analyze these accumulated data and evaluate the cardiovascular risk caused by blood pressure
variation.
References
Kario K, Nishizawa M, Hoshide S, Shimpo M, Ishibashi Y, Kunii O, Shibuya K. Development of
a disaster cardiovascular prevention network. Lancet. 2011; 378: 1125-7.
Nishizawa M, Hoshide S, Okawara Y, Shimpo M, Matsuo T, Kario K.
Aftershock Triggers Augmented Pressor Effects in Survivors: Follow-Up of the Great East
Japan Earthquake. Am J Hypertens. 2015 Apr 18. [Epub ahead of print]
2)Japan Morning Surge-Home Blood Pressure (J-HOP) Study
The aim of this study is to investigate the relationship between home BP and target organ damage and
cardiovascular outcome to make Japanese hypertension guideline. The patients with one more than
cardiovascular risk factor, 4566 subjects, have enrolled and followed up from 74 institutes.
References
Kario K, Hoshide S, Haimoto H, Yamagiwa K, Uchiba K, Nagasaka S, Yano Y, Eguchi K, Matsui Y,
Shimizu M, Ishikawa J, Ishikawa S; the J-HOP study group.
Sleep Blood Pressure Self-Measured at Home as a Novel Determinant of Organ Damage: Japan
Morning Surge Home Blood Pressure (J-HOP) Study. J Clin Hypertens (Greenwich). 2015 Feb 16.
Hoshide S, Kario K, Yano Y, Haimoto H, Yamagiwa K, Uchiba K, Nagasaka S, Matsui Y, Nakamura A,
Fukutomi M, Eguchi K, Ishikawa J; J-HOP Study Group.
Association of morning and evening blood pressure at home with asymptomatic organ damage in the
J-HOP Study. Am J Hypertens. 2014 Jul;27(7):939-47.
3)Japan Ambulatory Blood Pressure Prospective (JAMP) Study
The Japan Ambulatory Blood Pressure Prospective Study (JAMP study) began in January 2010. The
study aims to create an ABPM database from 10,000 high risk subjects with cardiovascular risk in Japan
to understand the status of blood pressure control by region and clarify for which the components of
24-hour blood pressure are important for predicting cardiovascular event, JAMP study will clearly
answer these questions in clinical practice. 6112 patients have been enrolled from 111 institutes.
References
Yano Y, Hoshide S, Tamaki N, Inokuchi T, Nagata M, Yokota N, Hidaka T, Kanemaru Y, Matsuda S,
Kuwabara M, Shimada K, Kario K. Regional differences in hypertensive cardiovascular remodeling
between fishing and farming communities in Japan. Am J Hypertens. 2011; 24:437-443.
4)Sleep Pressure and disordered breathing in REsistant Hypertension And Cardiovascular

Disease (SPREAD) Registry
We have developed a new device to detect sleep BP level triggered desaturation caused by sleep apnea
syndrome. The aim of this study is to study the relationship between frequency of sleep apnea
syndrome and nocturnal hypertension in the patients of refractory hypertensive and cardiovascular
disease by using the sphygmomanometers to measure the blood pressure surge due to the nighttime
hypoxia. In addition, the aim of this study is to identify the high risk patients and provide them the
optimal treatment from these results. The plan is to follow up the cases in this registry including of their
baseline data to investigate the causal relationship between the frequency of sleep apnea syndrome and
pathologies of blood pressure surge. Presently, 893 patients have been enrolled from 25 institutes.
References
Shirasaki O1, Kuwabara M, Saito M, Tagami K, Washiya S, Kario K. Development and clinical
application of a new technique for detecting 'sleep blood pressure surges' in sleep apnea patients based
on a variable desaturation threshold. Hypertens Res. 2011 Aug;34(8):922-8.
Division of Nephrology and Kidney Center, Department of Internal Medicine
Theme of research:
Cardiovascular complications in dialysis patients
The role of Klotho protein, anti-aging hormone, in CKD patients

Daisuke Nagata, Professor, nagatad@jichi.ac.jp
Shigeaki Muto, Professor, smuto@jichi.ac.jp
Osamu Saito, Associate Professor, nephsait@jichi.ac.jp
Tetsu Akimoto, Associate Professor, tetsu-a@jichi.ac.jp

Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease
(CVD). Dialysis patients in Japan have already exceeded 29,000 persons, and it is shown
that the patients with CKD including dialysis had higher mortality from CVD. The kidney
expresses Klotho gene, which may function as an anti-aging hormone. Klotho protein
which is a product of the Klotho gene, may decrease with the progression of CKD.
Therefore, we hypothesize that the Klotho protein is related to higher occurrence rate of
CVD in CKD patients. The role of Klotho gene or protein in the formation of the
arteriosclerotic lesion, bone and vascular complications in CKD patients, will be
investigated.
Division of Gastroenterology, Department of medicine
Theme of research:
Double-balloon endoscopy (#1)
Enodoscopic submucosal dissection for early gastrointestinal neoplasm (#2)
Clinical use of Flexible spectral Imaging Color EnhancementFICEand Blue Laser
Imaging (BLI) (#3)
Name of main researcher, title, and e-mail address
Hironori Yamamoto (#1.2.3), Professor, ireef@jichi.ac.jp
Hiroyuki Osawa (#3), Associate Professor, osawa@jichi.ac.jp
Presentation at medical conferences
Reporting to medical journals
Division of Pulmonary Medicine, Department of Medicine
Theme of research:
Impaired Toll-like Receptor-Mediated Inflammatory Response in the Alveolar
Macrophages of Streptozotocin-Induced Diabetic Mice
Hideaki Yamasawa, MD, hyamasa@jichi.ac.jp

Toll-like receptors (TLRs), that recognize conserved pathogen-associated molecular
patterns, play a role in the recognition of invading pathogens and initiate inflammatory
responses, including the production of proinflammatory cytokines. Diabetes mellitus is
often identified as an independent risk factor for the development of lower respiratory
tract infections. Alveolar macrophages (AM) constitute the first-line defense against
inhaled pathogens.
We therefore investigated the effect of hyperglycemia on
TLR-mediated proinflammatory cytokine production by AM.
Experimental
hyperglycemia was induced in Balb/c mice by the intraperitoneal injection of
streptozotocin. We have demonstrated that hyperglycemia impaired the responsiveness
of the alveolar macrophages to multiple TLR agonists by inhibiting the production of
proinflammatory cytokines. Our present interest is the mechanisms of these inhibitory
effects. Therefore we are conducting the further investigations focusing on the
hyperglycemia-induced alterations in intracellular signaling.
Division of Neurology, Department of Medicine
Theme of research:
Gene therapy for neurodegenerative diseases
Shin-ichi Muramatsu, Professor

Our research aims to develop novel therapies for major neurodegenerative diseases
such as Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS).
Gene therapy: After our successful preclinical research for a primate PD model via
stereotactic injection of AAV vectors expressing dopamine (DA)-synthesizing
enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC),
and GTP cyclohydrolase I, we are now conducting a clinical research of gene thrapy
for advanced cases of PD with a stereotactic intraputaminal injection of AAV-AADC
combined with oral L-DOPA administration. In transgenic ALS mice, our research of
intramuscular AAV-GDNF transfer exhibited protective effects on spinal motoneurons.
These methods using AAV vectors may offer novel and feasible treatment options in
neurodegenerative disease.
Cell therapy: Another interest of our research is regenerative medicine using primate
embryonic stem (ES) cells. By cultivating in astrocyte-conditioned medium, we
induced neural stem cells from primate ES cells, and have shown restoration of DA
function in a primate model of PD after transplantation of the neural stem cells.
Division of Hematology, Department of Medicine
Theme of research:
1) Molecular analysis of c-Cbl.
2) Analysis of anti-GVHD effects of MSCs.
3) Analysis of tumor supporting effects of MSCs
Takahiro Suzuki
Kazuya Sato
Iekuni Oh
Assistant Professor
Assistant Professor
Assistant Professor
tasuzuki@jichi.ac.jp
kazuya@jichi.ac.jp
norma@jichi.ac.jp

1) Recently, we and our collaborators found novel point mutations in a
proto-oncogene, c-cbl, in some samples derived from MDS patients. With the gene
mutations, mammalian cells can be transformed into tumor cells. We are
investigating the molecular mechanisms of transformation induced by these gene
mutations. We are also investigating the functions of c-Cbl for cytoskeletal regulation
using c-Cbl knockout mice.
2) 3) It has been reported that MSCs (Mesenchymal stromal cells) may potentially
attenuate GVHD after bone marrow transplantation. But molecular mechanisms of
immunomodulation by MSCs are still obscure. We are investigating the mechanisms
of MSC-mediated suppression of immune response by using in vivo murine
transplantation models. It is also known that MSCs can support hematopoietic
malignant cells. We also investigate tumor supporting effects of MSCs.
Publications
1) Suzuki T, Oh I, Ohmine K, Meguro A, Mori M, Fujiwara SI, Yamamoto C, Nagai T,
Ozawa K. Distribution of serum erythropoietin levels in Japanese patients with
myelodysplastic syndromes. Int J Hematol. 2015 Jan;101(1):32-6.
2) Okabe H, Suzuki T, Uehara E, Ueda M, Nagai T, Ozawa K., The bone marrow
hematopoietic microenvironment is impaired in iron-overloaded mice. Eur J
Haematol. 2014 Aug;93(2):118-28.
Division of Hematology, Department of Medicine
Theme of research:
1) Development of novel adaptive immune gene therapy for hematological malignancy

Ken Ohmine;
Assistant Professor
omineken@jichi.ac.jp
Iekuni Oh;
Assistant Professor
norma@jichi.ac.jp
Kiyoshi Okazuka
Clinical Associate
kokazuka@jichi.ac.jp
Adoptive immunotherapy with CD19-specific chimeric antigen receptor (CAR) gene transduced T cells has
been shown to be very promising for refractory hematologic malignancies. We are conducting a phase 1/2
clinical trial to evaluate the safety and efficacy of CD19-CAR-T in patients with relapsed or refractory
non-Hodgkin lymphomas. Patients autologous T cells were transduced with a retrovirus encoding a CAR
construct composed of anti-CD19 scFV linked to CD28 and CD3;signaling domain and expanded with
RetroNectin/OKT3 stimulation. Patients are administered cyclophosphamide as a lymphodepletion ending
two days before CAR-T infusion and receive either 1 x106 cells/kg (dose level 1), 3 x106 cells/kg (dose
level 2), or 1 x107 cells/kg (dose level 3) of CAR-T. Enrollment started in December 2014.
(Clinicaltrials.gov, identifier; NCT02134262).
Publications
1)
Uchibori R, Tsukahara T, Ohmine K, Ozawa K. Cancer gene therapy using mesenchymal

stem cells. Int J Hematol. 99(4):377-82, 2014.
2)
Ishihara A, Ohmine K, Weisbrode SE, Bertone AL. Effect of Intra-Medullar and

Intra-Venous Infusions of Mesenchymal Stem Cells on Cell Engraftment by In-Vivo Cell
Tracking and Osteoinductivity in Rabbit Long Bones: A Pilot Study. Orthop Muscular
Syst.3(3), 2014.
3)
Tsukahara T, Iwase N, Kawakami K, Iwasaki M, Yamamoto C, Ohmine K, Uchibori R,

Teruya T, Ido H, Saga Y, Urabe M, Mizukami H, Kume A, Nakamura M, Brentjens R,
Ozawa K. The Tol2 transposon system mediates the genetic engineering of T-cells with
CD19-specific chimeric antigen receptors for B-cell malignancies. Gene Ther.
22(2):209-15, 2015
Division of Endocrinology and Metabolism, Department of Medicine
Theme of research:
Neutral lipid metabolism and cardiometabolic diseases
Shun Ishibashi, Professor, ishibash@jichi.ac.jp

Obesity, diabetes and atherosclerosis are the leading causes of morbidity and mortality in
industrialized countries including Japan. These cardiometabolic diseases are characterized
by excessive accumulation of neutral lipids in various organs. For example, triglycertides
and cholesterol esters are accumulated in adipose tissues and vascular walls, respectively.
Therefore, elucidation of the mechanisms underlying the synthesis and hydrolysis of these
neutral lipids is important to understand the pathophysiology of the cardiometabolic
diseases and to develop new treatment for them. Previously, we generated mice lacking
acyl-CoA:cholesterol acyltransferase (ACAT) or hormone-sensitive lipase (HSL).
Phenotypic analyses of these mice led us to find new functions of these enzymes. By
bioinformatic approach, furthermore, we identified new members of neutral lipid esterase
family which are involved in adipocyte lipolysis(CES1) and cholesterol ester hydrolysis in
macrophages(NCEH1). One of them, for example, is substantially expressed in adipose
tissues and its expression is significantly correlated with adiposity in humans. We are now
trying to determine relative contribution these multiple enzymes to the neutral lipid
hydrolysis in adipocytes and macrophages. We are also examining whether inhibitors of
the neutral lipids inhibit the development of the cardiometabolic diseases using animal
models.
Theme of research:
Transgenic dissection of cholesterol biosynthetic pathway
Cholesterol biosynthetic pathway provides not only cholesterol (sterol pathway) but also
other derivatives with significant biological activities like isoprenoids, dolichol and
ubiquinone (non-sterol pathway). HMG-CoA reductase (HMGCR) is the rate limiting step
for both sterol and non-sterol pathway, while squalene synthase (SS) is the first committed
enzyme for sterol pathway. In order to define the role of these in enzymes in the
cholesterol homeostasis, we generated mice lacking HMGCR or SS in the liver or
macrophages using Cre/loxP technology. HMGCR is essential for survival and SS is
dispensable for cholesterol biosynthesis. We hope there results will help us develop better
pharmaceutical drugs than statins, which are widely used in the current clinical setting, to
treat lipid disorders and atherothrombotic diseases.
Theme of research:
Genetic analysis of metabolic diseases.
Significant proportion of plasma lipid levels is genetically determined. We are
performing genetic analyses of patients with these disorders, particularly focusing on
hyperchylomicrinemia syndrome and severe insulin resistance syndrome. In addition to
deficiency of lipoprotein lipase and apolipoprotein CII insulin receptor, apo AV and other
novel genes have emerged as the causative genes.
Division of Rheumatology and Clinical Immunology
Theme of research:
1) New Treatment of Rheumatoid Arthritis
2) Mechanism of RA Development in Human
3) Clinical Importance of MMT-3 in RA
4) Importance of Anti-CCP antibody in RA

1) Seiji Minota, Professor, MD, PhD: sminota@jichi.ac.jp
2) Masahiro Iwamoto, Associate Professor, MD, PhD: hiro-iwa@jichi.ac.jp
3) Takao Nagashima, Associate Professor, MD, PhD: naga4ma@jichi.ac.jp
4) Katsuya Nagatani, Associate Professor, MD, PhD: knagatani@jichi.ac.jp

1) Examining the effects of various drugs or supplements on the prevention of RA development
induced by immunization of collagen type II in mice. Also examining these drugs and materials on
the disease-abating effects after RA development.
2) Examining which gene(s) is expressed first during the development of human RA and pursuing the
possibility of the gene(s) to detect earliest relapse.
3) Examining clinical importance of the serum level of metalloproteinase 3 in RA patients and the
influence its serum levels under glucocorticoid-use.
4) Making human monoclonal anti-CCP antibody using lymphocytes from RA patients with a high
titer of it and pursuing the clinical significance of RA development in human.
Department of Dermatology
Theme of research:
The roles of epidermal keratinocytes in inflammatory skin diseases

Mayumi Komine, M.D., Ph.D., Associate Professor

1) Epidermis is the outermost tissue protecting human body from environmental
stresses, and responds to various kinds of environmental stimuli. We focus on the
role of epidermal keratinocytes responding to these environmental stimuli, such as
mechanical stress, ultraviolet light, microbes, and wounding.
2) Psoriasis is one of the inflammatory skin diseases, and various novel therapeutics
have been developed, however, the curative treatment have not been established. We
have outpatient psoriasis clinic, and try several clinical studies on psoriasis.
3) Many cutaneous diseases are inherited, and we try to identify the causative
mutations in patients of hereditary skin disorders, such as epidermolysis bullosa,
epidermolytic ichthyosis, palmoplantar keratoderma, and steatocystoma multiplex.
4) We have many patients with autoimmune bullous diseases. We are investigating the
signaling pathways provoked by antibody binding to epidermal keratinocytes, and
the following production of inflammatory cytokines.
5) Epidermal keratinocytes and vascular endothelial cells produce interleukin-33,
which works as an alarmin. We investigate the mechanism of production and the
role of IL-33 in inflammatory skin diseases and wound healing processes utilizing
IL-33 knockout mice, and mice models of inflammatory skin diseases.
Department of Radiology, Division of diagnostic and interventional radiology
Theme of research:
Cardiac radiology: Assessment the accuracy of dual source computed tomography (DSCT) to detect
cardiac coronary disease and left ventricular wall motion abnormalities.
Gastrointestinal radiology: Colorectal cancer screening using CT colonography (CTC).
Body MR imaging: MR imaging for cancer detection and characterization using non-contrast
technique.
Musculoskeletal radiology: The evaluation of bone erosions in Rheumatoid Arthritis with CT and MRI.
Neuroradiology: Unilateral amygdala enlargement with temporal lobe epilepsy
Head and Neck radiology: Multimodality imaging such as CT, MRI, and PET-CT of the head and neck
cancer.
Nuclear medicine: Impact of whole-body 18FDG-PET/CT on diagnosis of pulmonary mass lesions and
therapeutic management of lung cancer.
Pediatric radiology: Evaluation of radiation dose in pediatric CT and fluoroscopy
Interventional radiology: Efficacy of percutaneous trans-hepatic angioplasty with use of intravascular
ultrasound for portal venous complication after pediatric living donor liver transplantation.
Yuko Otake, MD., Clinical assistant professor, oh_yuko@jichi.ac.jp
Shigeyoshi Kijime, MD., Clinical assistant professor, kijimashige@yahoo.co.jp
Yukio Kimura, MD., Clinical assistant professor, yukio-k01@jichi.ac.jp
Takeshi Shinozaki, MD., Assistant professor, shinotak@jichi.ac.jp
Akifumi Fujita, MD., Assistant professor, akifuji@jichi.ac.jp
Rieko Furukawa, MD., Senior resident, rfurukawa@jichi.ac.jp
Waka Nakata, MD., Clinical assistant professor, waka-s@jichi.ac.jp
Shigeru Kobayashi, MD., Clinical assistant professor, skoba@jichi.ac.jp
Hideharu Sugimoto, MD., Professor and Chairman, sugimoto@jichi.ac.jp
Clinical research has been an important part of the Department of Radiology, Jichi Medical University
since the Dr. Sugimoto, professor and chairman had succeeded to the former chair. At present, the
faculty members of the department are engaging in various fields of diagnostic and interventional
radiology, even though the workload of the department is significantly increasing in the past 10 years.
In 2012, two 3.0 T MRI were installed. Now, we have 5 MR units, 4 high-end CT scanners, PET-CT
and SPECT-CT, and advanced angiographic units. Using this equipment, faculty members and fellows
are performing clinical researches. A part of the activity is listed in the theme of research. Further, we
had clinical MRI, CT, and DSA in the laboratory for the large animals, such as piglet.
Psychiatry
Theme of research:
1. The effect of 3,4-methylenedioxymethamphetamine ('Ecstasy') on monoamine
metabolism in the rat anterior hypotalamus: the role of dopamine and serotonin.
2. Effect of chronic interferon-alpha on extracellular dopamine and serotonin
concentrations in the rat prefrontal cortex.
3. Time series analysis of human electrocorticogram from subdural electrodes during
wakefulness and sleep.
4. NK cell activity and blood pressure in patients with mood disorder.
5. Evaluation of cerebral activity after social skills training to schizophrenic patients
by using fMRI and NIRS.
6. Study on the long-term courses of mood disorders.
7. Duration of untreated psychosis and 1 to 2-year outcome of first contact psychoses.
8. Effectiveness of multidisciplinary treatment system on eating disorder.
9. Transcultural psychiatric studies on the relationship of acculturation process to
mental health among Japanese Latin Americans in Japan.
10. Mental disorders and creativity.

Professor
Professor
Takaaki Abe
Otsuka Koichiro
Assistant professor
Toshiyuki Kobayashi e-mail : kabakun@jichi.ac.jp
Lecturer
Senichiro Kikuchi
Lecturer
Katsutoshi Shioda
Lecturer
Shiro Suda
Lecturer Masaki Nishida

We continue to develop various researches in the field of
1) biological psychiatry such as psychopharmacology, psychophysiology as well as
2) psychopathology such as social psychiatry, transcultural psychiatry, art therapies,
pathography(creativity), trying to bridge two approaches based on clinical
experience.
Department of Pediatrics
Theme of research:
Molecular studies of autism spectrum disorders; phenotype analyses, genetic variation
analyses and identification of sensitive genes.
Takanori Yamagata (Professor takanori@jichi.ac.jp), Hitoshi Osaka (Professor), Eriko
Jimbo (Associate Professor), Naomi Nakashima (Assistant Professor)

Autism spectrum disorder (ASD) is a developmental disorder characterized by the
affected social interaction including verbal development and stereotypic behavior. To
reveal molecular pathology of ASD, we have been working on the following projects.
(1) Candidate gene analyses for the disease-sensitive mutations
Both functional and positional candidate genes have been analyzed for their
disease-sensitive mutations on the patients with and without familial predisposition.
(2) Genomic microarray studies, comparative genomic hybridization (CGH) and copy
number variation (CNV), are also in progress.
(3) Phenotype genotype interaction
Phenotype genotype interaction is analyzed with association of Project (1).
(4) Animal model research
By using knockout mice for secretin receptor, Gpcrs and other genes in which disease
sensitive mutation was detected in Project (1), several projects are in progress
including behavior analysis, neuropathology and molecular studies.
Theme of research:
Chromosomal genomic hybridization (CGH) and candidate gene analysis for the patients
with multiple anomaly
Takanori Yamagata (Professor), Hitoshi Osaka (Professor), Yasuyuki Nozaki (Assistant
Professor)
Chromosomal micro-rearrangements such as micro-deletion or duplication have been
reported to be the cause of many diseases including mental retardation and multiple
anomaly syndromes. To detect the responsible genes for developmental disorders and/or
multiple anomalies including cardiac anomaly, we are analyzing the patients for microrearrangement by chromosomal genomic hybridization (CGH) method. And also we
analyze the candidate genes for mutations by direct sequencing.
Theme of research:
Elucidation of pathogenesis
osteoimmunological aproach
of
Langerhans
cell
histiocytosis
(LCH)
by

Akira Morimoto (Associate Professor, akira@jichi.ac.jp )

LCH is characterized by a proliferation of CD1a-positive LCH cells intervening with
activated T cells, macrophages, eosinophils and osteoclast like multinucleate giant cells,
and associated with the lesional cytokine storm. In the LCH lesions, it has been shown
that proinflammatory cytokines, chemokines and other proteins such as RANK-RANKL,
OPG play a role. Clinical features of LCH are quite variable from an osteolytic lesion
with single system to a fatal disease with multisystem involvements. To date, however,
either mechanism of LCH cells proliferation or role of these lesional cytokine storm
remains unknown We investigate the pathogenesis of LCH by using osteoimmunological
approach.
Theme of research:
Continuous Infusion of Cyclosporin A (CICyA) treatment for intravenous immunoglobulin
resistant Kawasaki disease (KD)
Takaomi Minami (Assistant professor), Tomoyuki Sato (Assistant professor),
Takanori Yamagata (Professor)
Intravenous immunoglobulin (IVIG) resistant KD patients had an increased risk of
developing coronary artery lesion compared with those with good response. Treatment of
intravenous immunoglobulin resistant KD is challenging. We employed CICyA in
IVIG-resistant KD patients.
The aim of our research is to disclose
1) effect of CICyA
2) side effect of CICyA and
3) mechanism of CICyA in patients with IVIG-resistant KD
Theme of research:
Treatment of genetic neurological disorders in childhood

Hitoshi Osaka (Professor), Takanori Yamagata (Professor)

Our understanding for molecular basis for genetic neuronal diseases is expanding.
However, our goal is not to diagnose but to treat children. Two main topics are focused.
1) Gene therapy: We aim to deliver adeno-associated viral (AAV) vectors, cloned
causative gene, to the central nervous system.
Large portion of genetic disorders in
childhood are caused by the functional loss of mutated gene, thus becoming good
candidates for AAV gene therapy.
AAV vector is safe and expresses cloned gene
lifelong without carcinogenesis, which makes itself as one of the most promising viral
vectors.
2) iPS cells: Patients derived iPS cell are now available. We are differentiating iPS cells
into cells with neuronal lineage. Disease phenotype appeared in iPS cells or
differentiated cells will be a good target for drug screening. The iPS cells are also useful
resources to evaluate the efficiency of viral gene delivery by AAV and to monitor the
toxicity of drugs before clinical trials.
We challenge, as one team, to find a novel treatment for devastating childhood
neurological diseases.
Theme of research:
Developing a new ultrasonic method for evaluating tissue characterization: For
diagnosing of non-alcoholic steatohepatitis
Hideki Kumagai (Associate Professor), Koji Yokoyama (Assistant Professor)
It is important to evaluate the condition of the liver for treatment decision-making
or prognostication. There has been a need to develop non-invasive, repeatable, and
accurate techniques for quantitative evaluation of tissue characteristics in the liver.
Diagnostic techniques that evaluate frequency attenuation or elasticity have been
developed in clinical setting, but evaluation based on sound speed or other image
parameter has not yet been applied clinically. Our ultimate goal is to develop a
non-invasive diagnostic technique capable of tissue characterization by measuring
the speed of sound or other new parameter in the liver.
Theme of research:
Mechanistic study on the pathogenesis of idiopathic steroid-sensitive nephrotic syndrome in
children
Takahiro Kanai, MD, PhD (assistant professor), Jun Odaka MD (assistant professor), Takane Ito
MD (assistant professor), Takashi Saito MD (assistant professor), and Jun Aoyagi MD (assistant
professor)
Idiopathic steroid-sensitive nephrotic syndrome (ISSNS) is one of the most common chronic
renal disease. Its characterized by edema, massive proteinuria, hypoalbuminemia and hyper
cholesterolemia. We have already revealed that CD4+ T cells play important roles in the
pathogenesis of this disease [1-9]. On the other hand, there is still a lack of understanding on
how CD4+ T cell could develop ISSNS. Were currently exploring the mechanisms by
elucidating the relationship between human CD4+ T cells and hyperlipidemia with biochemical
technology (FACS, proteomics), biogenetic technology (cDNA microarray, QT-PCR, ChIP-seq,
siRNA) and pathological technology (immune staining) using human samples.
1. Kanai T, Yamagata T, and Momoi MY. Macrophage inflammatory protein-1 and
interleukin-8 associated with idiopathic steroid-sensitive nephrotic syndrome. Pediatr Int. 51:
443-7: 2009.
2. Kanai T, Yotsumoto S, and Momoi MY. Norovirus-associated Renal Acute Renal Failure
with Nephrotic Syndrome. Pediatr Int. 52:e23-5: 2010.
3. Kanai T, Shiraishi H, Ito T, Odaka J, Saito T, Aoyagi J, Ueda Y, and Momoi MY. Plasma
exchange and tacrolimus therapy for focal segmental glomerulosclerosis collapsing variant
and the cytokine dynamics. Ther Apher Dial. 14; 603-605: 2010.
4. Kanai T, Shiraishi H, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J, and Momoi MY. Th2
cells predominate of idiopathic steroid-sensitive nephrotic syndrome. Clin Exp Nephrol. 14:
578-583: 2010.
5. Kanai T, Shiraishi H, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J, and Momoi MY.
Elevated serum interleukin-7 level on idiopathic steroid-sensitive nephritic syndrome. Pediatr
Int. 53: 906-9: 2011.
6. Odaka J, Kanai T, Ito T, Saito T, Aoyagi J, Momoi MY. Dense deposit disease with steroid
pulse therapy. Jichi Medical University Journal. 34: 97-102: 2012.
7. Jun Aoyagi, Takahiro Kanai, Takane Ito, Jun Odaka, Takashi Saito, Mariko Y. Momoi.
cytokine dynamics in a 14-year-old girl with tubulointerstitial nephritis and uveitis syndrome
CEN Case Reports DOI:10.1007/s13730-013-0084-z
8. Kanai T, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J et al. Apolipoprotein AII levels are
associated with the UP/UCr levels in idiopathic steroid-sensitive nephrotic syndrome.
Clinical and experimental nephrology. 2014.
Division of Gastroenterological and General Surgery, Department of Surgery
Theme of research:
Subdivision of Hepato-Biliary Surgery
Hideki,Sasanuma, Atsushi Shimizu, Yoshikazu Yasuda, Yasunaru Sakuma, Masanobu
Hyodo, Takehito Fujiwara, Yuji Kaneda, Atsushi Miki, Kazue Morishima, Naoya Kasahara,
Masanobu Taguchi, Yukihiro Sanada, Kazuhiro Endo
1. The relationship of the blood flow and pressure among the portal vein, the inferior vena
cava and the hepatic artery. An experimental study on pigs.
2. Immunohistochemical study of characteristics of bile duct dysplasia evaluated on the
basis of expression of metastasis/invasion-related factors and p53.
3. Swine model for training of living-related liver transplantation.
4. Hepatic arterial infusion chemotherapy for non-resectable colorectal liver metastasis.
5. Influence of simultaneous hepatic resection on left-sides colonic anastomosis.
6. The analysis of intra luminal blood flow of the portal vein by color-Doppler ultrasound.
7. Gene expression of drug induces hepatitis.
8. Liver regeneration
9. Islet transplantation
10.
11. Islet & Liver transplantation
Surgery, pathology1, physiology2
Theme of research:
1. Basic research of esophageal cancer
2. Ghrelin and gastric surgery
Main researcher Yoshikazu Yasuda
1.Shin Saito, Takashi Ui
2.Masaru Koizumi, Masanobu Taguchi
1. Saito S, et al: A clinicopathological study of basaloid squamous carcinoma of the
esophagus. Esophagus 6:177-181, 2009
2. Koizumi M, et al. Reconstruction-dependent recovery from anorexia and time-related
recovery of regulatory ghrelin system in gastrectomized rats. Int J Pept. 2010
3. Koizumi M, et al Postoperative weight loss does not resolve after esophagectomy despite
normal serum ghrelin levels. Ann Thorac Surg. 2011;91:1032-7.
Theme of research:
Immunohistochemical analysis of REG I expression in ulcerative colitis-associated
neoplastic lesions
Hiroyuki Tanaka,
Yoshikazu Yasuda,
Background and aims: The regenerating gene (REG) Ihas been identified by
microarray analysis as a gene that is distinctly overexpressed in ulcerative colitis, and its
protein product is suggested to play a pivotal role in the development of UC-associated
carcinoma. In the present study, we investigated the significance of REG I expression as
a diagnostic marker of UC-associated neoplasia.
Methods: Tissue samples were obtained from colectomy specimens from 31 patients with
long-standing UC (mean disease duration 17.2 years, range 5-29 years). The lesions were
evaluated according to the International Classification for Dysplasia in Inflammatory
Bowel Diseases, and the sections were examined using immunohistochemistry for REG I
and P53.
Results: In the regenerating atypia group, REG I immunoreactivity was restricted to
the lower third of the UC mucosa (Grade 1). Lesions classified as indefinite for
dysplasia also showed predominantly basal-type staining for REG I. However, in
low-grade dysplasia and high-grade dysplasia lesions, the localization of REG I
immunoreactivity expanded to the middle (Grade 2) and upper (Grade 3) third of the
UC mucosa, respectively. The REG I immunostaining pattern differed significantly (P
<0.0001) between non-neoplastic and neoplastic lesions, and was significantly (P
<0.0001) associated with p53 overexpression.
Conclusions: Immunohistochemical analysis of REG I expression is useful for
differential diagnosis of non-neoplastic and neoplastic lesions in UC tissues.
Theme of research:
Real and virtual 3D modeling of hepato-biliary-pancreatic disease
Naohiro Sata MD, PhD
Hideki Sasanuma MD PhD
Masaru Koizumi MD, PhD
Kazuhiro Endo MD
sata@jichi.ac.jp
h-ssnm@jichi.ac.jp
mkoizumi@jichi.ac.jp
kendo@jichi.ac.jp

3D modeling is a quite attractive solution for the safe surgical procedure. The aim of
this research is evaluation of feasibility of real and virtual 3D model from individual image.
From the dataset of MD-CT, individual volume-rendering virtual 3D image is created in the
workstation. 3D printer can produce real 3D model of the individual image by
post-processing of the dataset. The attendant surgeons would make preoperative simulation
of dissection with tactile sense using virtual 3D model. Real 3D model would offer many
novel possibilities in the surgical management, intraoperative navigation surgery, education
for young doctors, residents, and medical students, tools for informed consent, and so on.
This research would provide new aspect of diagnosis and management in
hepato-biliary-pancreatic disease.
Department of Surgery
Theme of research:
Liver functional and regenerational analysis of NAFLD with hepatectomy
Atsushi Miki M.D., Ph.D. amiki@jichi.ac.jp
Non-alcoholic fatty liver disease (NAFLD) or Non-alcoholic steatohepatitis (NASH) is a
cause of liver cirrhosis and hepatocellular carcinoma. And epidemiologically the number is
growing up gradually according to the change of life style in japan. In part due to improved
perioperative care, liver resection has become a standard therapy. However, the surgical
outcome in patients with liver cirrhosis remains a problem due to the higher mortality and
morbidity rate compared to operations on other organs. There are few reports about surgical
outcome of NAFLD or NASH patients.
We attempt to analyze the effect of steatohepatitis with surgical outcome and liver
regeneration with molecular biological approach using rodents.
Theme of research:
Preoperative estimation of liver functional reserve toward better outcome of hepatectomy
Atsushi Miki M.D., Ph.D., Yasunaru Sakuma M.D.,Ph.D., Yoshikazu Yasuda M.D.,Ph.D
The preoperative estimation of liver function is important to avoid post-hepatectomy liver
failure for hepatocellular carcinoma with hepatitis. However, it has been difficult to estimate
remnant liver functional reserve due to the variability of regional liver function and lack of
system analyzing regional liver function.
Recently 99-Tc galactosyl asialoglycoprotein receptor (GSA) scintigraphy reported to
calculate the regional liver function better than old style methods. Moreover recently new
GSA SPECT/CT machine is introduced in this institute, which could construct 3D image.
We try to estimate the regional liver function with GSA scintigraphy by the surgical
simulation on the computed software with the fusion image of the GSA scintigraphy SPECT
and computed tomography.
Theme of research:
Islet beta cell mass analysis with in-vivo imaging system
Atsushi Miki M.D., Ph.D. amiki@jichi.ac.jp
Islet cell transplantation is a promising therapy for brittle type I diabetes. Isolated islets are
transplanted into liver via portal vain. After transplantation, it could be difficult to assess the
number, viability, and function in vivo.
We generated a novel reporter system using secreted Gaussia princeps luciferase (GLuc)
under the control of a Pdx1 promoter, which was used as a transgene for the generation of
reporter mice to monitor Pdx1 promoter activity in vivo via the measurement of secreted
GLuc activity in a small aliquot of blood.
We are working to assess the islet beta cell mass and function in vivo.
Division of Cardiovascular Surgery, Department of Surgery
Theme of research:
Left ventricular remodeling after surgical treatment
Professor Yoshio Misawa,
tcvmisa@jichi.ac.jp

Left ventricular remodeling after surgical treatment in patients with left ventricular
volume overloading diseases such as aortic valve regurgitation or mitral valve
regurgitation is serially followed by UCG study. Optimal timing for these diseases is
discussed.
Division of Cardiovascular Surgery, Department of Surgery
Theme of research:
Cardiovascular surgery to elderly people
Shin-ichi Oki
The risk of an operation also increases with a cardiovascular patient's aging. Although the
fall of clear operation results now is not accepted by careful selection of surgical
indication as compared with a youth, expansion of surgical indication is needed with
increase of the number of elderly-people patients. The feature of a cardiovascular
operation of elderly people is grasped, and investigation of surgical indication is
performed.
Division of CV Surgery, Department of Surgery
Theme of research:
1. Development of left ventricular assist device
2. Biocompatibility, antithrombogenicity, and physiology of rotary blood pump
3. Clinical research of acute aortic dissection

Koji Kawahito, professor, kawahito@omiya.jichi.ac.jp

1. Development of left ventricular assist device. We have developed axial flow ventricular assist
device (VAD) in corporation with NASA/Johnson Space Center in Houston. This device named
Micromed/DeBakey VAD (formerly knowed as NASA/DeBakey VAD) is now used for permanent
ventricular assist in US and Europe.
2. We have been studying biocompatibility, antithrombogenicity, and physiology of rotary blood pump
from viewpoints of neutrophil activity, platelet activity, and proinflammatory cytokines.
3. We have been studying short term and long term surgical results of acute aortic dissection. The
focus of these studies are preoperative risk analysis, mechanism of malperfusion, and newly
developed surgical techniques.
Division of General Thoracic Surgery, Department of Surgery
Theme of research:
Vital observation of small pulmonary vessels in the rat with a soft X-ray system.
Shunsuke Endo, Professor and Chairman
Kenji TETSUKA, M.D., Assistant Professor
Vasoconstriction and vasodilatation of small pulmonary vessels (200~500) are very
important in regulation of pulmonary circulation. We developed a vital observation
technique for small pulmonary vessels in the rat lung by soft x-ray system. Now, we are
studying the mechanisms of hypoxic vasoconstriction by using this system.
Theme of research:
Drug delivery system via liquid ventilation
Shunsuke Endo, M.D.PhD.
Professor and Chairman

Alveolar recruitment can be completed using liquid ventilation after acute lung injury
where drug can not be sufficiently delivered due to derrangement of pulmonary
microcirculation. Efficacy of drug delivery system using liquid ventilation is evaluated by
visualization through a vital fluorescent microscopy.
Theme of research:
Control of polymorphonuclear leukocyte- endothelial interaction during surgical stress.
Shinichi Otani, Assistant Professor
During surgical stress, improper activation of PMN may contribute to local or global
tissue injury such as acute respiratory syndrome and multiple organ failure syndrome.
polymorphonuclear leukocyte-endothelial interactions play a central role in the pathogenic
process and could be a target for therapies to prevent or treat such injuries.
The aim of this research is to control polymorphonuclear leukocyte-endothelial interaction
during surgical stress. We developed a novel model of green fluorescent protein transgenic
rat for real time observation of PMN transit in pulmonary microcirculation.
Pediatric Surgery
Theme of research:
Pediatric Surgery
Shigeru Ono, Professor: o-shige@jichi.ac.jp

1) Study of cancer stem cell in children
2) New treatment strategy for tracheal stenosis
3) Development of new surgical technology in Pediatric Surgery
Division of Transplant SurgeryDepartment of Surgery
Theme of research:
1) Innovation of new organ preservation solution.
2) Selection of proper immunosuppressive agents by lymphoblast genesis.
3) Development of hepatic artery anastomosis by using microsurgical technique
1) Hideo Kawarasaki (Professor) kawarasaki@jichi.ac.jp
2) Koichi Mizuta(Associate Professor) koimizu@jichi.ac.jp
One hundred fifty two pediatric liver transplantation from live donor has been performed
at our institution since May, 2001. Our research work is strongly related to our daily
clinical activities.
1)University of Wisconsin(UW) solution is world wide available as an organ preservation
solution. As this solution is extra cellular type, this needs to be washed out just before
hepatic blood circulation. Intra cellular type preservation solution which needs not to be
irrigated has been innovated by us.
2)It will be possible to select proper immunosuppressive agent by this new method,
lymphoblast genesis.
3)As a size of the hepatic artery is small in children, hepatic artery stenosis and
thrombosis are often reported in pediatric liver transplantation. Microsurgical technique
enables us to perform safe anastomosis of the hepatic artery.
Department of Plastic Surgery
Theme of research:
Keloid biology
Ataru Sunaga, M.D.
atarusuna@me.com

We have just started a new project funded by a Grant-in-Aid for challenging Exploratory
Research by the Japanese Ministry of Education, Culture, Sports, Science, and
Technology.
The long term research goal of our lab is to understand the pathogenesis and the
pathophysiology of keloids.
Department of Neurosurgery
Theme of research:
Biological and electrophysiological study using congenital epileptic EL mice
Keiji Oguro, Hidenori Yokota, Eiju Watanabe
EL mouse is an epileptic model animal which develops temporal lobe epilepsy-like
attacks after 10W from birth. Our experimental purpose is to reveal the mechanisms
underlying temporal lobe epilepsy. By electrophysiological methods using hippocampal
slice of EL mice, we found out abnormal hyper-excitability in CA3 region which might
explain the mechanisms of temporal lobe epilepsy. Now we are trying to find further
molecular mechanisms which induce the hyper-excitability and to develop a new
therapeutic method for clinical field.
Theme of research:
Functional Brain Mapping Using Optical Topography for the Parkinsons Disease patients with Deep Brain Stimulation Therapy

Takeshi Nakajima, Eiju Watanabe

Introduction
Optical Topography (OT) can monitor the brain tissue oxygenation and its kinetics. Using OT, we have studied the hemodynamic
change of the brain and the regional activation as correspond to the cerebral blood volume (rCBV). Positron emission
tomography (PET) and single photon emission CT (SPECT) studies were previously reported that deep brain stimulation (DBS)
therapy for the Parkinsons disease patients, made rCBV change clinically. Former methods could detect only the steady state of
the hemodynamic conditions; we could measure the change of the rCBV continuously by the OT.
Methods
The subjects were nine Parkinsons disease patients treated DBS therapy for the bilateral subthalamic nucleus. The rCBV were
measured by 44-channel OT with both movement and recognition tasks. For the movement task, we employed the repeated
hand-grasping movement, and for the recognition task, did intentionally losing on the
Rock-Paper-Scissors. The Rock-Paper-Scissors, the way to win or lose, is a common game in Japan, like tossup in the world. The
rule is that rock win scissors, scissors win paper, but paper win rock. Then, people tend to win unconsciously despite of being
asked to lose. Losing Rock-Paper-Scissors need recognition and conflict, therefore we use this as recognition task as no-go
reaction. Study protocol was that patients were measured rCBV during movement task and recognition task with DBS off first,
then, they practiced the same tasks with DBS on and were examined again. All of these protocols were not easy to implement and
could be performed in about 30 to 40 minutes.
Results
Five patients were studied with motor tasks, and nine were with recognition tasks. About the motor functions, two of five patients
showed increase of rCBV at dominant frontal cortex or motor area by DBS on grasping task. In the other two patients of rest
three, rCBV of the interest area was decreased. In the recognition tasks study, rCBV of the normal volunteers tended to increase
at the lateral pre-frontal cortex of dominant side to the Losing Rock-Paper-Scissors tasks. Among the DBS patients, four of nine
were the same pattern as normal volunteers, but the other three responded opposite way, decreased rCBV were observed in the
corresponded cortex.
Discussion
In the patients whose rCBV were increased with DBS on, it seems that DBS made their CBV pattern normally and that lead
improving of their movement. On the other hand, patients that DBS could not make increase rCBV were thought that they had
already made increase their CBV during these tasks without DBS. Then, it is possible that DBS make their effort easier and they
did not need to make CBV increase. We could interpret that this could be an effect of STN-DBS, modification of rCBV for
normalizing pattern. The OT examination may be a useful tool for evaluation of the effect of STN-DBS.
Theme of research:
Assessment of cerebral ischemia by oxygen pulse-based near infrared optical
topography
Eiju Watanabe
Takehiko Konno
Toshihiro Mashiko
SPECT and angiography are methods used to assess the cerebral blood flow dynamics;
however they have several drawbacks such as physical stress on the patients and
invasiveness. In order to overcome these drawbacks, we proposed an alternative method
of using optical topography (OT).
We used a 48-channel OT system with 2 faces of 35 probe-holders on the patients
head covering the bilateral front-temporal areas. Measurements were performed at a
frequency of 10Hz. The subjects inhaled room air followed by oxygen for 2 minutes
and then room air again, and SpO2 were monitored at the subjects finger tips.
The level of oxy-hemoglobin measured by OT in normal brain regions showed a
trapezoid increase in accordance with oxygen inhalation, and similar results were
obtained for SpO2. In the ischemic regions, the oxy-hemoglobin increase was delayed
and/or its height was lowered. These observations suggest that transmission of the
systemic SpO2 wave pattern was delayed and lowered in the ischemic region; this
phenomenon can be utilized to detect cerebral ischemia. Our results suggested that the
regional attenuation of the oxy-hemoglobin wave reflects the ischemic state of cerebral
blood flow.
This method uses oxy-hemoglobin as a tracer of OT. It can be clinically utilized as a
real time and noninvasive assessment method for the assessment of cerebral ischemia.
Department of Orthopaedics
Theme of research:
Patient-based outcome measures for spine surgeries

Atsushi Kimura, M.D., Ph.D., akimura@jichi.ac.jp

Over the past decade, there has been increasing interest in the use of patient-based measures of
medical care. Patient-based measures include generic measures, disease-specific measures, and
measures of patient satisfaction. We prospectively investigate patient-based outcomes in patients
undergoing various spine surgeries. In particular, we are interested in chronic pain before and after
spine surgeries.
Department of Obstetrics and Gynecology
Theme of research:
Basic and clinical researches are under way in the three divisions: 1) Oncology, 2) Obstetrics, and 3)
Reproductive Endocrinology.

Matsubara S (chairman and professor),
1) Oncology: Fujiwara H (professor), Konno R (professor), Saga S (associate professor), Takei
Y(assistant professor), Machida S(assistant professor),
2) Obstetrics: Matsubara S (professor), Okuchi A (associate professor),Watanabe T (associate
professor), Usui R(associate professor), Kuwata T(associate professor),
3) Endocrinology: Suzuki T(associate professor)

The followings are under way.
1) Oncology: The basic and clinical researches have been performed for the gynecologic malignancies,
including ovarian and cervical cancers. As for ovarian cancer, we have been trying some new cancer
therapies such as the molecular targeted therapies in which the angiogenetic factors like VEGF, etc. are
suppressed for the purpose of anti-tumor effects and inhibition of the peritoneal dissemination, and in
addition the gene therapies in which the anti-angiogenetic agents, including HGF/NK4, soluble Flt-1,
etc. are supplied systemically by use of the adeno-associated vectors (AAV). In cervical cancer, to
establish the gene therapy targeted to E6. E7 proteins, we developed a model mouse using a cervical
cancer cell line, and we evaluated the therapeutic efficacy of AAV-based vector to suppress the E6, E7
proteins.
2) Obstetrics: To elucidate the relationship between cytokines/growth factors and the pathophysiology
of gestational hypertension. To characterize the blood coagulation mechanism in pregnant women. To
evaluate the maternal-fetal well-being by ultrasound. To establish the prediction method for the
occurrence of gestational hypertension. To characterize the relationship between maternal vaginal
bacterial flora and preterm delivery. To establish procedures to achieve hemostasis for postpartum
bleeding. To establish surgical technique for cesarean section for placenta previa.
3) Reproductive Endocrinology: anti-gamete immunity: analysis of the roles of anti-sperm or anti-zona
pellucida antibodies in fertilization and embryo development. sperm physiology: investigation of the
mechanism of sperm capacitation. Tubal infertility: study for the roles of several chemokines in
Chlamydia infection. IVF and ICSI: improvement of the fertilization rates and TLRS. Development of
minimally invasive surgery: ovarian drilling using transvaginal hydrolaparoscopy.
Division of Renal Surgery and Transplantation, Department of Urology
Theme of research:
1. Renal transplantation/Transplant immunology
2. Vascular access surgery for hemodialysis
3. Renal hyperparathyroidisms
4. Minimally invasive adrenal/renal surgery
5. Renal cell cancer in hemodialysis patients
1. Takashi Yagisawa, MD, PhD, Professor
2. Koji Nanmoku, MD, PhD, Assistant Professor
3. Takaaki Kimura, MD
1. Renal transplantation/Transplant immunology (clinical and basic researches)
(a) 2~3 renal transplants performed in a month
(b) Trial and evaluation of new immunosuppressive drugs
(c) ABO blood type incompatible transplantation
(d) Transplant organ tolerance
(e) Advanced surgical techniques such as vascular anastomosis and laparoscopic donor
nephrectomy
(f) Oppotunistic infections such as cytomegalovirus and EB virus after transplantation
(f) Oxalate and calcium metabolism in renal transplant and hemodialysis patients)
2. Vascular access surgery for hemodialysis and peritoneal access surgery for CAPD:
(a) 150~200 vascular access surgery performed in a year
(b) Advanced techniques using artificial vascular devices
3. Secondary hyperparathyroidisms in dialysis patients
(a) 3-4 parathyroid surgery performed in a month
(b) Relationship between the grade of hyperplasia and calcium sensing receptor
4. Minimally invasive adrenal/renal surgery
(a) Advanced retroperitoneoscopic surgery for adrenal tumor and renal cancer
(b) Retroperitoneoscopic (laparoscopic) donor nephrectomy
5. Renal cell cancer in hemodialysis patients
(a) Pathogenesis of renal cell cancer in dialysis kidneys (compared to cases with normal
renal function.)
Department of Urology
Theme of research:
Heterogeneity of bladder cancer
Tatsuo Morita, Professor
Heterogeneity of bladder cancer has been well documented with respects to biologic,
cytogenetic, and histologic properties. These evidences suggest the clonal evolution
which can sometimes be seen as heterogeneity within the tumor mass as the tumor grows.
Namely, in the process of tumor progression, acquisition of genetic alterations results in
divergent clones with heterogeneity in genotypes and phenotypes. We previously
reported that human bladder cancer cell line JMSU1 established from malignant ascetic
fluid in advanced bladder cancer patient showed morphological heterogeneity at the
initial culture in vitro. Therefore, JMSU1 at the first passage seems to contain divergent
clones which would reflect the clonal evolution developed during the tumor progression
in the bladder cancer patient. The purposes of our project are to establish the clones from
the first passage of human bladder cancer cell line JMSU1 to examine clonal
heterogeneity in terms of genotypes and phenotypes, and to evaluate the divergent clonal
evolution in the process of tumor progression.
Department of Otolaryngology-Head and Neck Surgery
Theme of research:
Head
and
Neck
Cancer
Biology of Cancer Cells

Identification of Cancer Stem Cells
Clinical Trial
Hiroshi
Nishino,
Professor,
e-mail: hiroshi@jichi.ac.jp

Biology of Cancer Cells
We have studied a biology of cancer cells. Especially IL-6 enhances invasion of cancer
cells. Now we study an affect of cytokines on a proliferation and invasion of cancer cells.
Identification of Cancer Stem Cells
An exist of head and neck cancer stem cells is little known. Biology of head and neck
cancer stem cells is also unknown. Now we have tried an identification of head and neck
cancer stem cells. An immunohistological approach is now going. In the near future we
will investigate a FACS method and study biology of cancer stem cells.
Clinical Trial
Voice, phonation, swallowing and visual acuity is very important on a quality of patients`
life. Many head and neck patients are not satisfied while they manage a daily life after
treatments. We have study a platinum based concurrent chemoradiation and a cetuximab
based bio-radiation for advanced head and neck cancer patients.
Department of Otolaryngology/Head and Neck Surgery
Theme of research:
#1 Signal transduction in Head and Neck Squamous Cell Carcinoma
#2 Gene therapy for Head and Neck Squamous Cell Carcinoma
Takeharu Kanazawa, Associate Professor: kanatake@omiya.jichi.ac.jp

Galanin and its receptors, GALR1 and GALR2, are known as tumor suppressor and
focused as therapeutic targets in head and neck squamous cell carcinoma (HNSCC).
Previously, we demonstrated that the function of signaling pathways of GALR1 and
GALR2. In HNSCC cells with silenced GALR1 and GALR2, we showed that
reexpressed GALR1 suppresseed tumor cell proliferation via the extracellular-regulated
protein kinase-1/2 (ERK1/2) -mediated effects on the cyclin-dependent kinase inhibitors
(CKI) and cyclinD1. On the other hands, in the GALR2-transfected HNSCC cells,
galanin suppressed proliferation and induced apoptosis. Galanin stimulation also
mediated decreased expression of cyclin D1 and increased expression of the CKI,
p27Kip1 and p57Kip2. These effects were similar to GALR1, but GALR2 also induced
caspase-3-dependent apoptosis, which was confirmed by Annexin-V staining and DNA
fragmentation analysis. Thus, we understood the function of GALR1 and GALR2 as
tumor suppressor, but the signaling pathway of GALR2 is still unclear. Our search is
currently focused on signal transduction of GALR2 and suicide gene therapy for
HNSCC using GALRs and adeno-associated virus vector.
Pediatric Otolaryngology Jichi Childrens Medical Center Tochigi
Theme of research:
Development of auditory central nervous system
Makoto Ito M.D.Ph.D Professor. makoto-ito@jichi.ac.jp
Anatomical plasticity of projections of central auditory system have been examined to determine
the effects of unilateral or bilateral deafness during early development.
Department of Ophthalmology
Theme of research:
1Innovation of the treatments for intraocular inflammation (uveitis)
2Pathogenesis and Treatment of Pterygium
Histopathologic Study of Meibomian Gland Dysfunction
Aging Research of Lacrimal Gland
3Strabismus, Amblyopia
4Cytokine profiling of the aqueous humor from patients with age-related macular degeneration,
retinal vein occlusion and diabetic retinopathy.
1Hidetoshi Kawashima, MD. & PhD., Professor & chairman, hidemeak@khaki.plala.or.jp
2Hiroto Obata, Associate Professor, obatah@jichi.ac.jp
3Shinji Makino M.D., PhD., makichan@jichi.ac.jp
4Hidenori Takahashi M.D., Ph D., Associate Professor, takahashi.hidenori8@gmail.com
1We are exploring new modalities, both medical and surgical, of the treatments for intraocular
inflammation (uveitis). We are in the process of standarizing monoclonal antibody therapy
(infliximab) for Behcets disease. Furthermore, surgical intervention conducted and evaluated
here includes transplantation of corticosteroid implants and vitrectomy for various
complications such as cystoid macular edema, epiretinal membrane, and so forth.
2Clinical research of strabismus and amblyopia based on binocular visual function.
*Prismatic treatment for infantile esotropia
*Long-term outcome of strabismus surgery
*Management of dissociated vertical deviation
*Rotatory fusion in superior oblique muscle palsy
*Abnormal head position in vertical strabismus
3To optimize the treatment of age-related macular degeneration, retinal vein occlusion and
diabetic retinopathy, we are examining multiplex cytokine assay of the aqueous humor or the
vitreous fluid from patients.
We already have over one thousand samples of the aqueous humor or the vitreous fluid from
those patients and cataract or epiretinal membrane surgery patients as a control.
Recent study demonstrated that VEGF concentration of the aqueous humor from cataract
surgery patients without posterior vitreous detachment is twice as high as those with posterior
vitreous detachment.
Department of Anesthesiology and Critical Care Medicine
Theme of research:
1) The mechanism of acupuncture on central nervous system
2) Clinical and experimental study on the spinal canala endoscopy
1) Hideaki Tamai, Graduate fellow, Tamaihide@jichi.ac.jp
2)Takashi Igarashi, Associate Professor, igat@jichi.ac.jp
1) Investigation of effects of acupuncture on CNS by animal model and clinical case study.
2) The study of the spinal canal endoscopy includes (1) clinical investigation in patients with
Refractory back pain and (2) experimental study on developing a new product using a swine.
Division of Intensive Care, Department of Anesthesiology & Intensive Care Medicine
Theme of research:
Sleep deprivation and delirium in critically ill patients.
Shin Nunomiya, MD. Professor and Director: nunomiya@jichi.ac.jp

Critically ill patients, especially being under mechanical ventilation, often suffer from
severe sleep deprivation, which can lead to the development of impaired cognitive
function, delirium. Since delirium itself is one of the independent risk factors of poor
outcome of patients in ICU, efforts that prevent and avoid the development of delirium
would have supreme importance for critically ill patients care. Moreover, early detection
of delirium and proper intervention should be done to make an improvement of intensive
care quality.
Theme of research:
Clinical features and early diagnosis of coagulopathy in patients with sepsis.

Kansuke Koyama, MD. Research Associate: k_koyama@jichi.ac.jp

Sepsis is a clinical syndrome that complicates severe infection and is characterized by
systemic inflammation which is frequently associated with coagulopathy. Inflammation
and coagulation may play a pivotal role in the pathogenesis of sepsis. Severe
inflammation in sepsis leads to tissue factor mediated activation of coagulation, which
results in widespread fibrin deposition, contributing the development of multiple organ
dysfunctions. Therefore, sepsis-induced coagulopathy may have 3 aspects: 1) an
exacerbating factor of systemic inflammation, 2) a vascular endothelial dysfunction as one
of the sepsis-induced organ dysfunctions, and 3) the etiology of multiple organ failures in
severe sepsis. However both diagnosis and treatment of septic coagulopathy have not been
determined. We currently investigate the time course of hemostatic biomarkers in patients
with sepsis to determine the cutoff values for the early diagnosis of septic coagulopathy.
We plan to identify the indication and appropriate timing of therapeutic intervention for
coagulopathy in patients with sepsis in future.
Theme of research:
Mortality and Prognostic factors in Patients with Hematological Malignancies admitted to
the Intensive Care Unit.
Shinshu Katayama, MD. Research Associate: shinsyu_k@jichi.ac.jp

Recently, mortality of critical ill patients, like severe sepsis and septic shock, who
admitted to the ICU are decreasing. But mortality of hematological malignant patients is
40-50%, presented still high mortality.
Nowadays, there are several studies described about mortality and predictable factor of
ICU death in Europe, but there are few studies conducted in Japan.
So, we aimed to investigate the mortality of hematological patient and evaluate prognostic
factors in our hospital.
Clinical Laboratory Medicine
Theme of research:
Medical Ultrasound
Nobuyuki Taniguchi, Professor, taniguch@jichi.ac.jp

We have been researched for over 10 years of ultrasonic tissue characterization, which is
the method to measure the ultrasonic properties of the human tissues. The measurements
of frequency-dependent attenuation, scatter intensity, and non-linear parameter were
already reported. The flow volume measurement, which is our original system, is another
title for our research. The flow volumes of the common carotid arteries by age and sex
were measured, and the variations by the examiners were estimated. Renal arterial flow
volume is our recent work using this method, which cover not only normal but also
diseased, which are compared with the measurements of conventional method. This
system has already equipped with the commercialized machine. Now recent target we
have is how can we make the comfortable ultrasound machine system. To make
examination easily, we made new bodymarker system that demonstrate the position and
direction of the transducer automatically. This system enable us to save examination time
in abdomen, neck and breast area. This system is applied to transvaginal scan.
Department of Clinical Laboratory Medicine
Theme of research:
A study on serum amyloid A protein
Toshiyuki Yamada, Professor, yamadanji@jichi.ac.jp

Serum amyloid A (SAA) is an acute phase reactant, an apolipoprotein in HDL, and a
plasma precursor of reactive amyloid fibrils. Researches are focused on the followings.
i)
The real function of SAA in physiological or inflammatory states.
ii)
The mechanism that SAA forms amyloid fibrils.
iii)
The influence of SAA on lipoprotein metabolism as a HDL apoprotein.
iv)
The merit of SAA as a clinical test.
Theme of research:
The development of tests for lipids and lipoproteins
Kazuhiko Kotani, Associate Professor kazukotani@jichi.ac.jp

The laboratory assessment of atherosclerosis in lifestyle-related diseases, such as
dyslipidemia, obesity, and diabetes mellitus, is important. We have developed the
atherosclerosis assessments using several novel tools, such as serum markers of oxidized
or inflammation-modified LDL and HDL particles.
Presently, to elucidate the clinical significance of the new oxidized LDL and HDL on
lifestyle-related diseases is in progress in our group. The comparison of these new tools
and traditional ones is a research topic. A final goal of these developments is a
contribution to the prevention and management of atherosclerosis.
Theme of research:
Risk of Bacterial Transmission by Ultrasonographic Probes
Destructive influence on bacterial biofilm by ultrasonic irradiation
Harumi Koibuchi, MD,PhD, Lecturer

Ultrasound probes can transmit bacteria from patient to patient. And bacterial
transmission can be almost completely prevent by wiping ultrasound probes with
ethanol-soaked paper towel. But disinfection with ethanol may cause degradation of
ultrasound probes.
Bacterial biofilms can cause the intractable infectious disease, particularly, in patient
who is inserted medical implant such as central venous catheter, urethral catheter and
ventilation tubes. Biofilms are composed of polysaccharides, proteins, and other nutrients
essential for microbial survival. Once biofilm is formed, antibiotics dont work well on
bacteria covered by biofilm. On the other side, ultrasonic irradiation have an influence in
chemical and biological on cell lines.
We have investigated destructive influence on bacterial biofilm by ultrasonic irradiation.
Some power of ultrasound can decrease in quantity of biofilm formed from
Staphylococcus epidermidis.
Theme of research:
Ultrasound image recognition and tissue characterization
Kei KONNO, Associate Professor, konnok@jichi.ac.jp

Ultrasound imaging is essential for modern medicine. It gives us a lot of information
about a patient through many kinds of image such as B-mode, Doppler and contrast
enhanced images. Among them, B-mode is the most important in the clinical setting, and
we usually make a diagnosis based on graphical patterns observed in B-mode image.
However, it includes more precise information about underlying tissue as a minute change
in echo texture (speckle pattern), which is recognized subjectively by some experts but
hard to be assessed objectively.
To extract such information from B-mode image by using various methods used in the
field of image recognition may lead to an innovation in ultrasound tissue characterization.
Theme of research:
The examinations of atherosclerosis and vascular Disease using physiological methods
Kazuhiko Kotani, Associate Professor, kazukotani@jichi.ac.jp

We research about non-invasive vascular examinations. For the development of clinically
useful methods to measure atherosclerotic conditions, we compare new non-invasive
methods with existing methods such as flow mediated dilation and arterial thickness
ultrasonically measured and pulse wave velocity.
Theme of research:
Vascular function and atherosclerosis

Michiaki Miyamoto, Research Assistant
We study vascular function and atherosclerosis in subjects with diabetes and dyslipidemia mainly
using ultrasonography, devices for measuring arterial stiffness or endothelial function, and
biomarkers.
Theme of research:
Mineralocorticoid and salt in kidney disease
Klotho-FGF23 axis in kidney disease
Yoshitaka Iwazu, Lecturer, iwazu@jichi.ac.jp
Renal fibrosis especially tubulointerstitial fibrosis is the final common pathway leading decreased
renal function. Salt or phosphate overload might induce tubular injury and interstitial fibrosis.
Researchers are focus on the followings.
i) Mechanisms of tubulo-intersititial fibrosis in mineralocorticoid/salt-induced hypertensive rats.
ii) Which of mineralocorticoid and salt mainly contributes to tubulointerstitial injury?
iii) Klotho-FGF23 axis as therapeutic target.
Oral and Maxillofacial Surgery
Theme of research:
1. Functional reconstruction of jaws after resection of oral cancer
2. Nature elucidation of disease in oral mucosa and new therapy.
3. Restoration of oral functions (chewing, speaking, swallowing) of cancer patients after surgery.
Yoshiyuki Mori, Professor,
mori-ora@jichi.ac.jp
Yoshinori Jinbu, Professor,

Tadahide Noguchi, Assistant Professor,
jinbu@jichi.ac.jp
noguchi@jichi.ac.jp

1. We investigate immediate functional reconstruction. Especially ''Bare bone graft'' after resection
of mandibular cancer.
2. We intend to elucidate the nature of various diseases in oral mucosa, classify diseases correctly
and establish new treatment procedure.
3. After resection on oral cancer, many patients lose oral functions such as chewing, speaking and
swallowing. We intend to evaluate the abilities of each patient, investigate the cause of those
defects and establish new rehabilitation programs.
4. Developing and evaluation of new approach of orthognathic surgery using distraction
osteogenesis in patients with severe maxillary and/or mandibular deformity.
Emergency & Critical Care Medicine
Theme of research:
Emergency Medical System
Masayuki Suzukawa, Professor, eccmsuzu@jichi.ac.jp

Japanese emergency medical system has a long history but the system itself has been tired
out and does not fit for new modern society and new technology. We are proposing the
medical control system for the pre-hospital care and examining the efficacy of various
components of medical control system, such as medical director governance, educational
system for paramedic, efficient use of ambulance cars, and systematic and practical
classification of emergency patients. Recently, we are working on the project of
introducing First Responder system to Japan.
Division of Community and Family Medicine, Center for Community Medicine
Theme of research:
1. Rural health
2. Community-based epidemiology
Professor Eiji Kajii MD, PhD, kajiieij@jichi.ac.jp
Professor Masami Matsumura MD, PhD, nephron@jichi.ac.jp
Professor Soichi Koike MD, PhD, koikes@jichi.ac.jp
Professor Shizukiyo Ishikawa MD, PhD, i-shizu@jichi.ac.jp
Professor Toyomi Kamesaki MD, PhD, kmskt@jichi.ac.jp
Associete Professor Junichi Mise MD, KHE02105@nifty.ne.jp
1. Rural health
Rural Health System in Japan and Rural Medical Education
Nakamura, T., Okayama, M., Aihara, M., Kajii, E.: Injury mortality and accessibility to emergency care in Japan : an
observational epidemiological study. Open Access Emergency Medicine 6: 27-32, 2014.
Takamura, K., Okayama, M., Takeshima, T., Fujiwara, S., Harada, M., Murakami, J., Eto, M., Kajii, E.: Influence of
salty food preference on daily salt intake in primary care. International Journal of General Medicine 7:205-210, 2014.
Takezako, Y., Ishikawa, S., Kajii, E.: Advance Directives in Japanese Nursing Homes. Journal of Pain Symptom
Management. 45: 63-70, 2013.
Harada, M., Okayama, M., Ae, R., Kojo, T., Aihara, M., Kajii, E.: A Study on Regional Disparities in Access to
Inpatient Care, Using the Gini Coefficient. General Medicine 13(1): 25-29, 2012.
Morita, Y., Kuroki, S., Lefor, A., Kajii, E.: Analysis of the Reasons for Visits to a Clinic on an Isolated Island. General
Medicine 13(1): 30-36, 2012.
Muramatsu, S., Aihara, M., Shimizu, I., Arai, M., Kajii, E. : Current Status of Kampo Medicine in Community Health
Care. General Medicine 13(1): 37-45, 2012.
2. Community-based Epidemiology
Hirose, H., Ishikawa, S., Gotoh, T., Kayaba, K., Kajii, E.: Lifestyle Risk Charts Illustrating the 10-year Risk of Death
in a Japanese Small Community: The JMS Cohort Study at Wara.
3657-622014
Ishikawa, J., Ishikawa, S., Kario, K., the JMS Cohort Study Inverstigator Group: Relationships between the QTc
interval and cardiovascular, stroke, or sudden cardiac mortality in the general Japanese population. Journal fo
Cardiology Jul 24, 2014 ( pii: S0914-5087 (14) 00160-9. doi.org/10.1016/j.jjcc.2014.05.008).
Kakehi, E., Kotani, K., Ishikawa, S., Goto, T., Kayaba, K., Nakamura, Y., Kajii, E.: Relationship between screening
plasma glucose concentrations and cancer-and all-cause mortality: the Jichi Medical School(JMS) cohort study. Journal
Public Health 22: 505-511, 2014 ( doi: 10. 1007 / s10389-014-0643-6).
Kaneda, Y., Ishikawa, S., Gotoh, T., Kayaba, K., Yasuda, K., Kajii, E.: Risk of Cerebral Infarction assessed by Fasting
Insulin and Fasting Glucose in a Japanese General Population: The Jichi Medical School Cohort Study.
36: 33-40, 2014.
Yamamoto, R., Ishikawa, S., Mizooka, M., Kajii, E.: The prevalence of Helicobacter pylori with hypertension: The

JIchi Medical School Cohort Study. Jichi Medical University Journal 35:13-18, 2013.
Yano, Y., Kario, K., Ishikawa, S., Ojima, T., Gotoh, T., Kayaba, K., Tsutsumi, A., Shimada, K., Nakamura, Y., Kajii, E.
and The JMS Cohort Study Group : Associations Between Diabetes, Leanness, and the Risk of Deaths in the Japanese
General Popuraton: The JIchi Medical School Cohort Study. Diabetes Care
Dec 18, 2012 (Epub ahead of print).
Ishikawa, S., Kotani, K., Kario, K., Kayaba, K., Gotoh, T., Nakamura, Y, Kajii, E. and The JMS Cohort Study Group :
Inberse association between serum lipoprotein(a) and cerebral hemorrhage in the Japanese population. Thromb Res.
Epub Dec.20, 2012.
Sawabe, M., Tanaka, N., Mieno, MN., Ishikawa, S., Kayaba, K., Nakahara, K., Matsushita, S.; JMS Cohort Study
Group : Low lipoprotein(a) concentration is associated with cancer and all-cause deaths: a population-based cohort
study (the JMS cohort study). PLoS One. 7(4):e31954. Epub 2012 Apr 2, 2012.
Baba, Y., Ishikawa, S., Amagi, Y., Kayaba, K., Gotoh, T., Suzuki, M., Kajii, E.: Cardiovascular disease risk factors and
menopausal status: a study of 2467 Japanese women as part of the Jichi Medical Cohort Study. General Medicine.
2012; 13 .
Yamamoto R, Ishikawa S, Mizooka M, Kajii E. and JMS Cohort Study: Helicobacter pyirori Infection and
High-density Lipoprotein Cholesterol in Japanese Women; the JMS Cohort Study.
General Medicine 13(2): 93-102,
2012.
3. Others
Nakashima, Y., Kenzaka, T., Okayama, M., Kajii, E.: A case of thyroid storm with cardiac arrest. International Medical
Care Reports Journal 7: 89-92, 2014.
Kenzaka, T., Okayama, M., Fujiwara, S., Takeshima, T., Kumada, M., Kamesaki, T., Eto, M., Harada, M., Takamura,
K., Kajii, E. and The Jichi Community Genetics Team.: Analysis of regional differences in the expression frequency of
salt-sensitive genes in Japan. Experimental & Clinical Cardiology 20(10): 6523-6536, 2014.
Takeshima, T., Kumada, M., Mise, J., Ishikawa, Y., Yoshizawa, H., Nakamura, T., Okayama, M., Kajii, E. : Reasons
for encounter and diagnoses of new outpatients at a small community hospital in Japan: an observational study.
International Journal General Medicine 7: 259-269, 2014 (Jun 5;7:259-69. doi: 10.2147/IJGM.S62384. eCollection
2014).
Matsumoto, M., Koike, S., Matsubara, S., Kashima, S., Ide, H., Yasunaga, H.: Selection and concentration of obstetric
facilities in Japan: Longitudinal study based on national census data. Journal of Obstetries and Gynaecology Research
July 2, 2014 (doi: 10.1111/ jog.12663).
Takeshima, T., Okayama, M., Harada, M., Ae, R., Kajii, E.: Effects of disclosing hypothetical genetic test results for
salt sensitivity on salt restriction ehavior. International Journal of General Medicine. 6: 361-368, 2013.
Okayama, M., Takeshima, T., Ae, R., Harada, M., Kajii, E.: Primary care patient willingness for genetic testing for
salt-sensitive hypertension: a cross sectional study. BMC Family Practice 14: 149, 2013.
Nakashima, Y., Harada, M., Okayama, M., Kajii, E.: Analgesia for pain during subcutaneous injection: effectiveness of
manual pressure application before injection. International Journal of General Medicine 6: 817-820, 2013.
Takezako, Y., Ishikawa, S., Kajii, E.: Advance Directives in Japanese Nursing Homes. Journal of Pain and Symptom
Management
Epub Aug 25, 2012.
Kenzaka, T., Okayama M., Kuroki, S., Fukui, M., Yahata, S., Hayashi, H., Kitao, A., Kajii, E., Hashimoto, M.: Use of
a semiquantitative procalcitonin kit for evaluating severity and predicting mortality in patients with sepsis. International
Journal of General Meicine 5: 483-488, 2012.

Kenzaka, T., Okayama, M., Kuroki, S., Fukui, M., Yahata, S., Hayashi, H., Kitao, A., Sugiyama, D., Kajii, E.,
Hashinomo, M.: Importance of Vital Signs to the Early Diagnosis and Severity of Sepsis: Association Between Vital
Signs and Sequential Organ Failure Assessment Score in Patients with Sepsis. Internal Medicine 51: 871-876, 2012.
Kenzaka, T., et al. : Importance of vital signs to the early diagnosis and severity of sepsis: association between vital
signs and sequential organ failure assessment score in patients with sepsis. Intern Med. 2012; 51: 871-876.
Division of Cell and Molecular Medicine, Center for Molecular Medicine
Theme of research:
Understand life by light
Satoshi Nishimura, MD, PhD, Professor, snishi-tky@umin.ac.jp
In the physiological and pathological conditions, complex cellular interplay takes place in
living animals. However, conventional microscope approach using two dimensional
analysis was not sufficient for analyzing in cell dynamics and functions in vivo. Thus, we
improved in vivo imaging technique by custom-designed two photon microscopy, and
multi-color cytometry system for metabolic and thrombotic disease evaluation. In this
system, we identified single blood cells in circulating vessels, and we combined intravital
visualization and light-based cell manipulation to reveal the multicellular processes in
diseased conditions.
Research field is very broad. Please refer to our recent papers as bellows:
Thrombus and platelet
:
Nishimura et al, 2012 Blood.
Nishimura et al, 2010 JCI.
Thrombopoiesis
:
Nishimura et al, 2015 J Cell Biology.
iPS and platelet
:
Takayama, Nishimura et al. 2012 J Exp Med.
Nakamura, Nishimura et al. 2014 Cell Stem Cell.
Metabolic Diseases
:
Nishimura et al, 2007 Diabetes.
Nishimura et al, 2008 JCI.
Nishimura et al, 2009 Nat Med.
Nishimura et al, 2013 Cell Metabolism
Nishimura et al, 2014 Diabetes.
Heart Diseases
:
Seo, Nishimura et al. 2015 Prog Biophys Mol Biol.
Seo, et al. 2014 PNAS
Seo, et al. 2014 Circ Res
We are very welcome to foreign students with broad backgrounds: medicine, biology,
engineering, informatics, and optics. Communicating with English is okay in my labs. You
can freely access two-photon microscopy systems and understand life directly.
Division of Stem Cell Regulation, Center for Molecular Medicine
Theme of research:
1) Stem Cell Biology
2) Molecular Genetics and Epigenetics of Cancer
1) Yusuke Furukawa, M.D., Professor of Medicine, furuyu@jichi.ac.jp
2) Jiro Kikuchi, Ph.D., Associate Professor, kiku-j@jichi.ac.jp
3) Taeko Wada, Ph.D., Research Associate, twada@jichi.ac.jp
1) We investigate the regulatory mechanisms of cell cycle and cell death of hematopoietic
and cancer stem cells in order to provide the rational basis of safe and effective clinical
application.
2) We attempt to clarify the underlying mechanisms of carcinogenesis and
leukemogenesis by investigating the alterations of oncogenes and tumor suppressor
genes at the genetic and epigenetic levels.
Division of Genetic Therapeutics
Theme of research:
Gene transfer using various vectors, especially AAV vectors
Hiroaki Mizukami, MD, PhD, Professor, miz@jichi.ac.jp
We have been working with Adeno-associated virus (AAV) vectors, which have
ideal features for human gene therapy. As for the basic research of AAV vectors, utility of
AAV serotypes and various cis-elements have been systematically evaluated. We have
also optimized conditions concerning AAV-mediated RNAi in order to knockdown gene
expression in vivo. Moreover, we have established assay systems to measure immune
responses related to gene transfer and expression. Notably, assay system for neutralizing
antibody (NAb) has been sufficiently improved for preclinical and clinical studies.
Based on these basic research activities, we are exploring possible applications of
AAV vector- mediated gene therapy in the following categories. (I) Neurological
disorders: We have demonstrated a large number of applications using AAV-mediated
gene transfer into various locations of central nervous system, from mice to humans. In a
series of studies against Parkinsons disease, after success with animal models, a clinical
trial has been performed successfully (Joint research with the Division of Neurology and
the Department of Neurosurgery). (2) Genetic disorders: One of the most important
candidate disease in this category is hemophilia, especially hemophilia B. We
demonstrated long-term expression of factor IX in the therapeutic level following
intravenous vector injection in monkeys. Careful selection by NAb status is essential
before enrolling the study, suggesting the importance of the NAb screening in the future
human trials (Joint research with the Division of Cell and Molecular Medicine). (3) Eye
diseases: Retina is a good target for AAV-mediated gene transfer. We demonstrated the
efficacy of soluble flt gene transfer to prevent disease progression in diabetic retinopathy
in a rat model (SDT rat). (4) Malignancy: Indirect cancer gene therapy by the suppression
of tumor angiogenesis, metastasis, and dissemination are investigated. We developed a
model mouse with lymphatic metastasis, and demonstrated suppression of lymphatic
metastasis using gene therapy with AAV-sflt4 vectors targeting VEGF-C.
These results, along with the success in this field worldwide, suggest that
AAV-mediated gene transfer must play a crucial role in medicine in the near future.
Genetic Therapeutics
Theme of research:
Development of a novel reinforced adoptive immune-gene therapy for malignant lymphoma

Tomonori Tsukahara, PhD, Assistant Professor, ttsukahara@jichi.ac.jp
We are focusing on developing a novel reinforced adoptive immune-gene therapy using
genetically engineered autologous T lymphocytes expressing a chimeric antigen receptor
targeting CD19, for the treatment of refractory B-cell malignant lymphoma. For
pre-clinical studies, we are evaluating the ability of engineered T lymphocytes to
recognize and kill CD19 positive-tumor cells in vitro and Xenograft mouse models.
Futhermore, we are exploring new ways to improve the therapeutic efficacy of engineered
T lymphocytes.
Division of Genetic Therapeutics
Theme of research:
Safe gene engineering of the human genome by a viral gene integration machinery
Masashi Urabe, Assistant Professor, murabe@jichi.ac.jp

The adeno-associated virus (AAV), a member of parvovirus has a unique property
that it preferentially inserts its genome into the AAVS1 site on chromosome 19
(19q13.4), one of safe harbors for transgene insertion. The use of the AAV
integration machinery enables AAVS1-specific insertion of a given DNA sequence.
Insertion of foreign DNA to a defined site is prerequisite for safe genetic manipulation
of human cells since random integration of foreign DNA, for example, by retrovirus
vectors can give rise to insertional mutagenesis.
iPS cells can be applied for a lot of therapeutics in regenerative medicine.
However, forced reprogramming of somatic cells to generate iPS cells and their ability
to proliferate indefinitely raises the concern about their oncogenic potential. If iPS
cells have a suicide gene, iPS cells even after malignant transformation can be
selectively eliminated by the simple activation of the suicide gene. We are currently
developing iPS cells with a suicide gene at AAVS1. The use of iPS cells with a
fail-safe system should accelerate clinical applications of iPS cells.
Division of Anti-aging Medicine
Theme of research:
To understand molecular mechanisms of aging process

Hiroshi Kurosu,PhD.Associate Professor, kurosu23@jichi.ac.jp
Kazuhiro Shiizaki, MD,PhD. Lecturer, shiizaki@jichi.ac.jp
Makoto Kuro-o, MD,PhD. Professor, mkuroo@jichi.ac.jp
Our laboratory focuses on translating basic research on molecular mechanism of aging into
development of effective interventions in age-related diseases. We have identified novel endocrine
axes mediated by Klotho and FGF, which regulate mineral and energy metabolism. Our major
research interest is to establish the Klotho-FGF endocrine axes as novel targets for diagnosis and
treatment of chronic kidney disease.
Center for Molecular Medicine
Division of Regenerative Medicine
Theme of research:
Pigs, pigs, let them in for medical research!
Prof. Yutaka Hanazono, MD, PhD, hanazono@jichi.ac.jp

Our laboratory has engaged on three projects.
1) The derivation of hematopoietic stem cells from human iPS cells: We are generating
hematopoietic stem cells from human iPS cells in vivo in large animals such as sheep and
mini-pigs in order to address the shortage of donors for hematopoietic stem cells.
2) Pig models: We are generating mini-pig models for human diseases, such as severe
combined immunodeficiency (SCID), which would more closely resemble humans.
3) Genome editing: We are genetically modifying mouse, pig, and human cells with
CRISPR/Cas9 to model or treat human diseases.
The projects all include pig matters! The use of pigs or sheep is a unique feature of our lab,
but conventional experimental animals such as mice are of course used. I would like to
invite foreign post-graduate students to participate in these projects. Please come and join
us!
Division of Inflammation Research, Center for Molecular Medicine
Theme of research:
Role of the Inflammasome in Cardiovascular Disease and Metabolic Disorder
Masafumi Takahashi, Professor, E-mail: masafumi2@jichi.ac.jp

The major objective of my laboratory is to determine how inflammatory responses occur
in cardiovascular disease and metabolic disorder, and to development new treatments for
these diseases, including atherosclerosis, myocardial infarction, heart failure, diabetes,
nonalcoholic fatty liver disease (NAFLD), and hyperlipidemia. In particular, we are
currently focusing on a newly discovered innate immunenity pathway known as the
inflammasome. Our group recently found that the inflammsome plays an important role
in the pathophysiology of vascular injury, atherosclerosis, and myocardial infarction, and
demonstrate that the inflammasome acts as an initial sensor for the sterile inflammatory
response in cardiovascular disease.
Division of Biology, Center for Molecular Medicine
Theme of research:
Animal models for genetic diseases
Kiyoshi Kawakami, Professor
Hiroshi Yajima, Assistant Professor
Shigeru Sato, Associate Professor
Hiroki Sugimoto, Assistant Professor
Masanori Takahashi, Assistant Professor
By using inheritable genetic manipulation technique, we have developed several animal
models of human diseases. One is Na,K-ATPase (sodium pump) alpha subunit gene
knockout mouse, and the other is Six gene knockout mouse.
The sodium pump is the enzyme responsible for the maintenance of Na+ and K+ gradients
across the cell membrane. Adult mice heterozygous for the alpha2 subunit mutation
showed augmented fear/anxiety behaviors and late-onset hyperphagia, emphasizing those
heterozygous mice to be the model animal for lifestyle diseases. In addition, mutations of
a2 subunit gene are causative for familial hemiplegic migrane (FHM2). Mice harboring
mutations found in the patients have been established and are currently investigated
whether they are useful for disease model. We have recently established alpha3 subunit
knock out mice. The 3 subunit gene mutation is related to rapid-onset Dystonia
Parkinsonism (RDP). We have been elucidating whether the knockout mouse is an animal
model for RDP.
Branchio-oto-renal (BOR) syndrome is an autosomal dominant developmental disorder
characterized by the association of branchial arch defects, hearing loss, and renal
anomalies. It is recognized as one of the common forms of autosomal dominant hearing
impairment. Mutation in Six1 as well as Six5 were identified as causes of BOR. Mice
homozygous for Six genes mutation (Six1, Six4, and Six5) showed various defect in
development of sensory organs, cranial ganglia, and kidney. We will focus how Six gene
product regulate sensory organ formation.
Theme of research:
Roles of Six genes in organogenesis
Shigeru Sato , Associate Professor
Masanori Takahashi, Assistant Professor
Organogenesis is a precisely orchestrated process that is directed by the cell-intrinsic and
-extrinsic cues. Genetic ablation of Six1 and Six4 genes in mice caused multiple defects in
development of various organs; olfactory epithelium, inner ear, cranial ganglia, spinal
ganglia, skull, jaw, tongue, thymus, skeletal muscles, skeletons and kidneys. Since these
organs have different origins and architectures, Six genes should play distinct roles in each
organ formation. We explore common or specific functions of Six genes in the formation
of these organs, using molecular biological approaches, anatomical / histological analyses
and cell / tissue / organ / whole-embryo culture techniques.
We found aberrant primary sensory neuron-like cells within the spinal cord of Six1/Six4
double knockout mice. Since intramedullary sensory neurons are thought to be an
ancestral form of sensory neurons and not generated in the amniote, Six genes also appear
to be involved in the evolution of trunk sensory system.
Our final goal is to understand how do the same Six transcription factors play distinct roles
in different organogenesis and to get an evolutionary insight into the function and
regulation of Six genes.
Division of Biology
Theme of research:
Molecular and developmental mechanisms of placode formation
Shigeru Sato, Associate Professor,

Sensory placodes are ectodermal thickenings found in the head of vertebrate embryos that
give rise to cranial sensory organs (eye, nose and ear). Several transcription factors
including Six and Eya families are expressed in sensory placodes and in a common
precursor region for all placodes (PPR) and are essential for sensory placode formation.
Mice deficient for Six1 or Eya1 show severe malformation in the ear and nose while
mutations in human SIX1 and EYA1 are known to cause branchio-oto-renal (BOR)
syndrome. To understand the molecular and developmental mechanisms of sensory
placode formation, we have identified various placode-specific enhancers that activate Six
and Eya gene expressions by comparative genomics combined with in vivo enhancer
analyses using model animals. By using these enhancers as a tool, we are analyzing 1) the
gene cascade controlling PPR/placode formation, 2) the cell lineage of PPR and placodes,
3) the role of PPR/placode cells in the head development and 4) the evolutionary origin of
vertebrate placodes.
Theme of research:
Development of therapy for muscle dystrophy
Shigeru Sato , Associate Professor

Muscle satellite cells are known to play key roles in the skeletal muscle regeneration. To
understand how the proliferation and differentiation of muscle satellite cells are
orchestrated in order to regenerate the skeletal muscle, we are investigating the expression
and function of Six genes in the muscle satellite cells in vivo and in vitro.
The involvement of Six genes in the muscle regeneration has not been demonstrated,
although they have been shown to be required for the skeletal muscle development. The
expressions of Six1, Six4 and Six5 were maintained throughout the proliferation and
differentiation of muscle satellite cells isolated from the skeletal muscle of adult mice.
Overexpression of Six1 facilitated the differentiation of muscle satellite cells. In contrast,
overexpression of Six4 and Six5 inhibited the proliferation and differentiation of them.
The muscle satellite cells derived from Six4/ Six5/mutant mice were capable to
proliferate more rapidly than those from wile-type mice. There results suggest that Six
genes regulate the proliferation and differentiation of muscle satellite cells.
Our goal is to improve the symptoms of muscular dystrophy by manipulating the
expression of Six genes.
Theme of research:
Brain patterning and brain asymmetry
Masanori Takahashi, Assistant Professor, mtaka@jichi.ac.jp
1) Subdividing the brain primordium into distinct regions is a crucial strategy to generate different
types of neurons and glial cells at precise positions in the embryonic brain. I study molecular and
cellular mechanisms of brain patterning and neuronal differentiation in the mouse/rat embryo
using the techniques such as whole embryo culture, electroporation for transferring exogenous
genes into brain progenitor cells, and confocal laser-scanning time-lapse imaging.
2) Regionalization of the brain and localization of the function at postnatal and adult stages are
also important issues in developmental neurobiology. To elucidate the question how functional
brain asymmetry is established in the mammalian brain, I am focusing on the relationship between
the left-right asymmetric gene expression and handedness identified by food-reaching tasks.
Division of Human Genetics, Center for Community Medicine
Theme of research:
Genetic study of lifestyle-related diseases
Sadahiko Iwamoto (Professor; siwamoto@jichi.ac.jp)
Kazuhiro Nakayama (Assistant Professor; nakayama@jichi.ac.jp)
We have established several human population genome resource banks, which were
attached with the data of anthropometric and metabolic parameters. The genome banks
were consisted with multiple Asian ethnic groups, Japanese, Mongolian, Chinese, Thai
and Palauan. Using these genome banks, we are performing genetic-epidemiological
analysis mainly through the SNP based population genetics and have succeeded in
identifying candidate loci associated with lifestyle-related diseases.
We are also performing molecular analysis about the genetic alteration, which is
identified through the genetic study. In order to show whether the gene or SNP associated
with lifestyle-related diseases results in a functional alteration, in vitro or in vivo gene
transduction study is employed routinely.
Department of Public Health
Theme of research:
Epidemiology of intractable diseases in Japan
Yosikazu Nakamura, Professor, nakamuyk@jichi.ac.jp
Nobuko Makino, Associate professor, n-makino@jichi.ac.jp
Epidemiologic studies on several intractable diseases have been conducted in Japan
every year under financial support by the Ministry of Health, Labour and Welfare. Our
department manages the data from those epidemiologic studies. Our research topics
regarding descriptive epidemiology of the intractable diseases were described below;
Neurofibromatosis
Myasthenia gravis
Primary sclerosing cholangitis
Precocious puberty
Theme of research:
Epidemiology of prion diseases
Yosikazu Nakamura, professor, nakamuyk@jichi.ac.jp
A research committee of prion diseases has been registered patients with prion diseases,
such as Creutzfeldt-Jakob disease, in Japan since 1999. More than 100 patients a year, or
about 90% of patients in this country, were registered. Our department plays a part of
epidemiologic analyses of the data registered.
Theme of research:
Epidemiology of cardiovascular diseases
Shizukiyo Ishikawa, Associate professor, i-shizu@jichi.ac.jp

Several early studies demonstrated the protective effect of light to moderate alcohol
consumption on cardiovascular diseases. As part of JMS (Jichi Medical School) Cohort
Study which has been conducted in twelve communities in Japan, association between
alcohol consumption and risk of cardiovascular diseases were investigated. Alcohol
consumption and risk of stroke revealed dose-response relationship, and modest alcohol
consumption reduced the mortality from all causes.
Theme of research:
Epidemiology of cardiovascular diseases
Shizukiyo Ishikawa, Associate professor, i-shizu@jichi.ac.jp

Dietary pattern analysis has emerged as a possible approach to estimate whole dietary
behaviors of study subjects in nutritional epidemiologic studies. As part of JMS (Jichi
Medical School) Cohort Study which has been conducted in twelve communities in
Japan, association between dietary patterns and risk of cardiovascular diseases were
investigated. In our previous study, dietary patterns were related to risk factors for
cardiovascular diseases (blood pressure and cholesterol level). Further prospective study
regarding cardiovascular diseases are in progress.
Theme of research:
Epidemiology of Kawasaki disease

Kawasaki disease is an acute systemic vasculitis of unknown etiology. Children aged 4
year or younger mainly suffered from this disease. The main purpose of the treatment
for the disease is to prevent developing coronary artery abnormalities. Nationwide
epidemiologic surveys on Kawasaki disease have been conducted in Japan almost every
two years since 1970. The data from those surveys were maintained in our department.
Our research topics regarding Kawasaki disease epidemiology were described below;
Chronologic and geographic change of incidence rate of Kawasaki disease

Mortality after suffering from Kawasaki disease
Risk factors for coronary artery abnormalities
Familial cases of Kawasaki disease
Risk factors for treatment failure for Kawasaki disease

Jichi Medical Research Overview 2015

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Division of Anatomy, Bio-imaging and Neuro-cell Science

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Uchibori R, Tsukahara T, Ohmine K, Ozawa K. Cancer gene therapy using mesenchymal

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