T MiMS
Tokyo Metropolitan Institute of Medical Science2017

Contents
03........ Message from Our Director

05 ....... History • Our Mission
06 ....... Our Strategies • Our Goals
07........ Organizational Chart • Our People at a Glance

Research Activities
08........Protein Metabolism Laboratory................Keiji Tanaka

Department of Genome Medicine
11........Genome Dynamics Project......................Hisao Masai
13........Mammalian Genetics Project...................Yoshiaki Kikkawa
15........Viral Infectious Diseases Project..............Fumihiko Yasui
17........Neurovirology Project...............................Satoshi Koike
19........Allergy and Immunology Project..............Takachika Hiroi
21........Molecular Medical Research Project......Futoshi Shibasaki

Department of Dementia and Higher Brain Function
23........Dementia Research Project.....................Masato Hasegawa
25........Learning and Memory Project.................Minoru Saitoe
27........Neural Prosthesis Project.........................Yukio Nishimura
29........Parkinson’s disease Unit..........................Makoto Hashimoto
30........Structural Neuropathology Unit................Toshiki Uchihara

Department of Brain Development and Neural Regeneration
30........Developmental Neuroimmunology Project....... Hiroshi Sakuma
33........Synaptic Plasticity Project........................Kanato Yamagata
35........Neural Development Project....................Haruo Okado
37........Neural Network Project.............................Nobuaki Maeda

Department of Psychiatry and Behavioral Sciences
39........Mental Health Promotion Project.............Atsushi Nishida
41........Schizophrenia Research Project.............Makoto Arai
43........Affective Disorders Research Project......Yoshitaka Tatebayashi
45........Sleep Disorders Project............................Makoto Honda
47........Addictive Substance Project....................Kazutaka Ikeda
01

Department of Sensory and Motor Systems
49........Motor Disorders Project............................Shinji Kakei
51........Visual Research Project...........................Takayuki Harada
53........ALS Nursing Care Project........................Yuki Nakayama
55........Diabetic Neuropathy Project....................Kazunori Sango

Department of Advanced Science for Biomolecules
57 .......Calpain Project.........................................Hiroyuki Sorimachi**Deceased; taken over by Yasuko Ono

59........Ubiquitin Project.......................................Noriyuki Matsuda
61........Stem Cell Project......................................Takahiko Hara
63........Regenerative Medicine Project................Yuichiro Miyaoka
65........Stroke Renaissance Project.....................Takashi Shichita
67........Biomembrane Unit....................................Kohji Kasahara

Research Support
68........ Center for Basic Technology Research
69........ Technology Licencing Office

70........ Center for Medical Research Cooperation
71........ Laboratory of Neuropathology

73 ....... TMiMS Programs
74........ Access Map

02

Message from Our Director
Director Keiji Tanaka
Metropolitan Tokyo is the center of Japan,
and I believe that Tokyo’s evolution into a
healthy and welfare-spirited city will contribute significantly to the realization of a richfuture for Japan. Our mission at the Tokyo
Metropolitan Institute of Medical Science(TMiMS) is to contribute to the improvementof health, medicine, and welfare of thenation’s capital by promoting life sciences
research.
Unprecedented progress in the life sciences in our modern era has
stripped away the veils hiding life’s mysteries one by one. Even so,
this does not mean that we have yet uncovered the full scope of theoperating principles that generate life. Humanity, as it has acquired
highly sophisticated biological systems that have evolved over long
eons, has encountered various problems that have arisen due tothat sophistication. Evolution on its own has not been sufficient tocounter these problems, necessitating the study of basic and appliedsciences.
While we admire the elegance of the mechanisms of life that ourcurrent wisdom is not yet fully able to elucidate, we know that the
breakdown of these sophisticated mechanisms leads to various
diseases. Furthermore, when we consider the inevitable andconstant instances of new diseases that arise due to the randomnessof gene mutation, we realize that humanity’s fight against disease will
be a permanent struggle. To overcome illnesses, it will be essential
to determine the pathogenesis of complex diseases, and develop
novel methods of manipulating biological pathways, including theimmune-response system, the linchpin of our biological defense
system. To do this, we need a full understanding of the basic biological mechanisms that give us life.
It is well-known that Japan has one of the world’s most rapidly aging
societies. Here in Tokyo—a microcosm of the entire nation—we havewitnessed a steady increase in the rates of various illnesses such as
cancer—our species’ nemesis—, infectious diseases, and conditions
that accompany aging, including brain and mental disorders. While
overcoming these diseases is certainly one of humanity’s common
goals, and has been the target of a number of national level initiatives, Tokyo, as a global city, must also strive to take a leading role inthis effort. Moreover, Tokyo is facing a growing number of challenges
that affect large metropoles. For example, although research intorare diseases is generally not a top-priority, Tokyo is home to many
people suffering from these diseases. TMiMS aims to protect thehealth of the capital’s populace through proactive research into basic
biological mechanisms, as well as research on diseases and other
health-related problems affecting Tokyo.

03

When we examine the history of science, we see how the development of new technologies has transformed our world, most notably during the industrial revolution. In the latter half of the twentieth century,
the advent of molecular biology radically altered our understanding of the biological sciences, leading to
the birth of the new age of scholarship.
Science and technology are constantly advancing, and no matter how sophisticated, past technologies
are soon surpassed by new innovations. It is through this constant progress that science has come toserve as a foundation buttressing social development. The growth of humanity and our inheritance of theresults that have been achieved through original research provide the driving energy to lead us towards aprosperous future. Likewise, the sustainable transmission of excellent research and training to next-generation personnel, who will support future research, will guarantee our institute’s future survival. If we wereto avoid this challenge and stand idly by, the institute would lose the very foundation of its existence. Whatis essential is that we create an attractive institute that will be able to nourish the hopes and dreams ofyounger generations.
It is my own personal belief that research is a symbol of culture, and our aim at TMiMS is to bring
together top scientists whose research will contribute to Tokyo's excellence, both academically andculturally. Academic research is often broadly divided into top-down translational research (appliedresearch) and bottom-up basic research (which may not have immediate applications, but is carried out
with an eye to the future). At TMiMS, we strive for a flexible style of organizational management thatcan benefit from the additive and synergistic effects of both of these strategies. These two strategies are
not antithetical to one another and do not entail a trade-off that precludes collaboration and integration. In
fact, throughout history, we find examples of research that at first glance seemed useless, but wasquickly transformed into practical research through innovative thinking to seize the world’s attention with amajor contribution to society.
Medical researchers at TMiMS tackle ambitious research challenges around the clock to develop new
methods to treat and prevent illnesses to “Ensure a Healthy Tomorrow.” While they are also responsible
for educating students and the general public, they simultaneously produce concrete research outcomes.
To aid in this effort, we provide them with the latest state-of-the-art technologies, and support the life
sciences at the broadest level, from basic to applied research. It is paramount that TMiMS grow as
an institute that conforms to the world’s highest standards and makes broad social contributions. The
guidance and encouragement of the citizens of Tokyo and of our partners will be essential to TMiMS’s
successful development. I thank you for your current and future support.

04

History
The Tokyo Metropolitan Institute of Medical Science (TMiMS) was established in April 2011 as aresult of the merger of three institutes; the Tokyo Metropolitan Institute for Neuroscience, the Tokyo
Metropolitan Institute of Psychiatry, and the Tokyo Metropolitan Institute of Medical Science, allof which had been founded in e a r l y - t o mid-1970s with the support of Tokyo Metropolitan
Government and had been located at different locations in Tokyo. The scientists from threedifferent disciplines got together in a new research building in a quiet residential area at
Kamikitazawa in Setagaya-ku, about 15 minutes by train from Shinjuku. The institute is under
the continuous support from the Tokyo Metropolitan Government, and our aim is to contribute to
medical advances and improve the health and welfare of people living in the metropolises
through collaborative research in basic life sciences, medical sciences, social medicine, andnursing.

Our Mission
The mission of our institute is to pursue research that will lead tothe development of solutions for health-related problems commonly
observed in large urban areas and developed countries. Utilizing
results from the forefront basic research on molecular and cellularmechanisms of biological pathways and disease pathology, we will
collaborate with municipal hospitals and clinics to predict, prevent, andtreat health problems. We will also identify causes of unsolved diseases and develop drugs and therapies for them. Our mission is also toprovide help and care with those suffering from serious diseases suchas ALS to better the patients’ quality of life. It is also our mission to
analyze the mental disturbances of the public and provide care and treatment.

05

Our Strategies
In a metropolis such as Tokyo, people suffer from various diseases and other health-related
problems unique to urban life-styles. These include mental disturbances caused by stresses
associated with daily life, diseases associated with longevity, and diseases caused by complicatedgenetic traits. We are studying these problems using a unique combination of disciplines,
technology and expertise.
We conduct forefront basic research invarious biological fields including genome
and protein functions, genetic diseases,
brain functions, neurobiology, neurodegeneration, stem cells and development,
virus infection, allergy, schizo-phrenia,
and depression. Using the state-of-art andnewest technology and equipment, we are
identifying molecules and mechanisms
responsible for disease progression andbiological phenomena. This knowledge
and technology will be used to predictand prevent diseases, and develop new
drugs and therapies that can be tailored
to individual patients.
We are also combining sociomedical approaches with molecular and genomic approaches todiscover unique and effective treatments for mental disorders. Our institute takes advantage of amulti-disciplinary structure to provide novel solutions to various health-related issues. Located in
one of the biggest cities in the world, we hope to be a role model for medical research institutes in
the coming decades.

Our Goals
To pursue research that will help prediction, prevention,
diagnosis, and treatment of various diseases andimprove the care of patients, leading to longer healthy life.
To serve as a leader and model institute for the life/medical
science in the coming decades.

Mt. FujiTokyo Skytree

Organizational Chart

Takahiko Hara

Our People at a Glance

As of December 1, 201707

Laboratory
Head

Keiji Tanaka Protein Metabolism Laboratory

Protein Metabolism:

The Ubiquitin Proteasome System

Tsuchiya, H., Ohtake, F., Arai, N., Kaiho,
A., Yasuda, S., Tanaka, K., and Saeki,
Y. (2017) “In vivo ubiquitin linkage-type
analysis reveals that the Cdc48-Rad23/
Dsk2 axis contributes to K48-linked
chain specificity of the proteasome.”
Mol. Cell 66, 485-502.
Ohtake, F., Saeki, Y., Ishido, S., Kanno, J., and Tanaka , K. (2016) “TheK48-K63 branched ubiquitin chain
regulates NF-κB signaling.” Mol. Cell
64, 251-266.
Yoshida, Y., Yasushi Saeki, Y., Murakami, A., Kawawaki, J., Tsuchiya, H.,
Yoshihara, H., Shindo, M., and Tanaka,
K. (2015) “A comprehensive methodfor detecting ubiquitinated substrates
using TR-TUBE.” Proc. Natl. Acad.
Sci. USA. 112, 4630-4635.
Pack, Chan-Gi., Yukii, H., Toh-e, A.,
Kudo, T., Tsuchiya, H., Kaiho, A., Sakata, E., Murata, S., Yokosawa, H., Sako,
Y., Baumeister, W., Tanaka, K., andSaeki, Y. (2014) “Quantitative live-cell
imaging reveals molecular dynamics
and cytoplasmic assembly of the 26S
proteasome.” Nature Commun. 5,4396
Koyano, F., Okatsu, K., Kosako, H., Tamura, Y., Go, E., Kimura, M., Kimura, Y.,
Tsuchiya, H., Yoshihara, H., Hirokawa,T., Endo, T., Fon. E.A., Trempe, J.F.,
Saeki, Y., Tanaka, K., and Matsuda,
N. (2014) “Ubiquitin is phosphorylated
by PINK1 to activate parkin.” Nature
510,162-166.
Saeki, Y., Toh-e, A., Kudo, T., Kawamura, H., and Tanaka, K. (2009) “Multiple
proteasome-interacting proteins assist
the assembly of the yeast 19S regulatory particle.” Cell 137, 900-913.
Murata, S., Sasaki, K., Kishimoto, T., Niwa, S., Hayashi, H., Takahama, Y., andTanaka, K. (2007) “Regulation of CD8+
T cell development by thymus-specificproteasomes.” Science 316, 13491353.
Hirano, Y., Hendil, K.B., Yashiroda, H.,
Iemura, S., Nagane, R., Hioki, Y., Natsume, T., Tanaka, K., and Murata, S.
(2005) “A heterodimeric complex that
promotes the assembly of mammalian
20S proteasomes.” Nature 437, 13811385.

All proteins of the cell continually are recycled with individually distinct
life-span, which is fundamentally important to keep healthy cellular
activities in eukaryotes. The proteasome, in collaboration with theubiquitin system used for choice of target proteins, selectively degrades
unnecessary proteins that must be eliminated from the cells. Indeed, theubiquitin-proteasome system (UPS) plays a pivotal role in the control
of a diverse array of basic cellular functions by catalyzing a number ofreactions timely, rapidly, and irreversibly. The missions of our laboratory
aim to elucidate the molecular mechanisms of the UPS and to integrate
it into physiology and pathology.

Research Projects
The Proteasome
1. Structure and Assembly of Proteasomes
The 26S proteasome is a highly organized and sophisticated proteolytic
nanomachine that degrades ubiquitylated proteins in an ATP-dependent
fashion. (Fig. 1). One longstanding question is how the complex structureof the proteasome is organized with high fidelity. During the past decade,we have succeeded in structural analysis of the 20S and 26S proteasomes. Further, we identified approximately 10 proteasome-dedicatedassembling chaperones (i.e., CP and RP chaperones) that assist in
the efficient formation of 20S and 26S proteasomes. Of them, we havedetermined the tertiary structures of almost all CP and RP chaperones,
displaying the mechanisms underlying proteasome assembly at theatomic levels. Based on these findings, we have established a model inwhich multiple dedicated chaperones govern proteasome assembly.
Figure 1. The 26S proteasome

The 26S proteasome consisting of a 20S
core/catalytic particle (CP) and one or
two 19S regulatory particles (RP). The
CP (alias 20S proteasome) is composedof four heptameric rings, which are madeup of seven structurally related a and b
subunits, displaying an α1-7β1-7β1-7α1-7 organization. The RP recognizes ubiquitylated
proteins, deubiquitylates for recycling of
ubiquitin, and then unfolds and translocates them into the interior of the CP for
degradation.

Protein Metabolism
08

2. Roles of Specialized Proteasomes in Cell-mediated Immunity
The proteasome has acquired diversity of the catalytic β subunits, which have evolved during theacquisition of adaptive immunity. To date, we have discovered the vertebrate-specific alternative 20S CP,
which we named the "immunoproteasome" and the “thymoproteasome” (Fig. 2). Whereas the immunoproteasome plays a specialized role as a professional antigen-processing enzyme in cell-mediated immunity,
the thymoproteasome is involved in the development of CD8+T cells in thymus; i.e., it has a key role in
the generation of MHC class I-restricted CD8+T cell repertoire during thymic selection called positive
selection.

Figure 2.
The immuno- and thymo-proteasomes

The immunoproteasome has catalytic subunits β1i, β2i, and β5i replacing β1, β2,and β5 and enhances production of MHC-I
ligands. The thymoproteasome contains thymus-specific subunit β5t in place of β5 or β5i
and plays a pivotal role in positive selectionof CD8+ T cells.

3. Spatio-temporal Dynamisms of the Proteasome
Little is known about the molecular dynamics of the proteasomes in living
cells. We measured the absolute concentration, dynamics, and complex
formation of the proteasome by quantitative live-cell imaging and quantitative
proteomics analyses. We found that the 26S proteasome is a highly mobile
complex and enriches in the nucleus. The 26S proteasome appears tocomplete its assembly process in the cytoplasm and then translocatesas a holoenzyme into the nucleus. Furthermore, we also found that theproteasome dynamically changes its subcellular localization and its cofactors
under various stresses. This might be a novel cellular response for adapting
to stress by regulating protein homeostasis.

The Ubiquitin System

Yasushi Saeki

1. Developing Methods to Decipher the Ubiquitin Code
Ubiquitylation is involved in numerous important cellular processes such as proteasomal degradation,
DNA repair, protein sorting, and signal transduction. The ubiquitin function is relied on eight structurally
distinct ubiquitin chains of different lengths, but our knowledge of the relationship between their topology
and functional outcomes is still insufficient. To understand the ubiquitin code, it is essential to develop new
methods for analyzing linkage types, chain lengths, and complexity of ubiquitylation.

Figure 3.
The Cdc48/p97-RAD23 axis is a major route to the proteasome

Proteasomal degradation is mainly regulated by indirect substrate sorting pathway by the ubiquitin-selective chaperone Cdc48/p97 and the
shuttling factors Rad23 and Dsk2.

09

Hikaru TsuchiyaWe have developed a highly sensitive MS/MS-based quantification method for ubiquitin chains. The
method allows us to analyze linkage-type selectivity of ubiquitin decoder proteins at endogenous
experimental setting. We recently identified the main pathway targeting the K48-linked ubiquitylated
substrates for proteasomal degradation (Fig. 3). We are further analyzing the decoder proteins throughout
the ubiquitin-mediated pathways to reveal the ubiquitin network.
2. Roles of Novel Ubiquitin Codes
Using quantitative mass spectrometry, we recently identified multiple chemical modifications of ubiquitin
itself. Acetylation of ubiquitin inhibits the elongation of particular ubiquitin chains, whereas phosphorylationof S65 ubiquitin stimulates ubiquitin chain synthesis for mitophagy. More recently, we identified more
complexed ubiquitin chains branched at K48 and K63. The K48/K63 branched chains act as a uniquecoding signal that specifically affects recognition by downstream reader proteins to enhance NF-κB
signaling. These novel ubiquitin codes greatly expand ubiquitin functions. We further explore additionalroles and regulatory mechanisms of these novel ubiquitin codes.

Fumiaki Ohtake

Figure 4.
The K48/K63 branched ubiquitin chains regulate NF-κB signaling pathway
Upon IL-1β stimuli, two ubiquitin ligases, TRAF6 and HUWE1 cooperatively assemble K48/K63 branched chains to amplify NF-κB signaling.

On-going Projects
1. Regulations of the proteasome to adapt to environmental stress

2. Exploring proteasome cofactors as therapeutic targets

3. Generation of mouse models of proteasome-related diseases
4. Developing methods to analyze ubiquitin chain architecture

5. Roles of the branched ubiquitin chains in protein degradation and signaling

10

Department of Genome Medicine
Project
LeaderHisao Masai Genome Dynamics Project

Genome Replication and Maintenance:
In search for unexplored message of the genome

You, Z. and Masai, H. (2017) “Potent
DNA strand annealing activity associated with mouse Mcm2~7 heterohexamer complex.” Nucleic Acids Res.
45,6495-6506.
Yang, C-C., Suzuki, M., Yamakawa,
S., Uno, S., Ishii, A., Yamazaki, S.,
Fukatsu, R., Fujisawa, R., Sakimura, K.,
Tsurimoto, T., Masai, H. (2016)“Claspin recruits Cdc7 kinase for
initia-tion of DNA replication in humancells.” Nature Commun. 7, 12135.
Kanoh, Y., Matsumoto, S., Fukatsu, R.,
Kakusho, N., Kono, N., Renard-Guillet,
C., Masuda, K., Iida, K., Nagasawa,
K, Shirahige, K, and Masai, H. (2015)“Rif1 binds to G-quadruplexes andsuppresses replication over long
distances.” Nature Struct. Mol. Biol.
22, 889-897.
Yamazaki, S., Ishii, A., Kanoh, Y., Oda,
M., Nishito, Y. and Masai, H. (2012)“Rif1 protein is a key regulator of the
genome-wide DNA replication timing
in human cells.” EMBO J. 31, 31673177.
Hayano, M., Kanoh, Y., Matsumoto,S., Shrahige, K. and Masai, H. (2012)“Rif1 is a global regulator of timing of
replication origin firing in fission yeast.”
Genes and Development 26,137-150.
Matsumoto, S., Hayano, M., Kanoh. Y.
and Masai, H. (2011) “Multiple pathways can bypass the essential roleof fission yeast Hsk1 kinase in DNA
replication initiation.” J. Cell Biol. 195,387-401.
Masai, H., Matsumoto, S., You, Z.,
Yoshizawa-Sugata, N. and Oda, M.
(2010) “Eukaryotic DNA replication;
where, when and how?” Annual Rev.
Biochem. 79, 89-130.

Precise duplication of genetic materials is central to the stable maintenanceof genomes through generations. Defects in the genome copying
processes would generate genomic instability which could ultimately
result in various diseases including cancer. The goal of our studies is tounderstand the molecular basis of how the huge genomes are accurately
replicated and the precise copies of the genetic materials are inherited
to the next generation. Three billion base pairs of the human genome (2meter long) are replicated with almost no errors during the 6-8 hr timespan of the cell cycle. This requires an extreme level of coordinationof temporal and spatial arrangements of chromatin organization andsignaling events for initiation of DNA replication.

“We are trying to decipher ‘unexplored message’of the genome that may play crucial roles inshaping the chromosomes, copying and readingout the information, and even in causing detrimental diseases.”
We recently discovered novel and crucial roles of non-standard DNA
structures in regulation of DNA replication and transcription. Notably, we
found that G-quadruplex structures, which are widely present on genomes(more than 370,000 on the human genome), regulate organization ofchromatin architecture and initiation of DNA replication. Our major
goal is to establish a novel principle of the genome by elucidating thefundamental and universal functionsof G-quadruplex and other non-B
type DNA structures in regulation ofvarious genome functions.
Through these efforts, we will also
explore the possibility that mutations
found in various diseases including
cancer are related to alterationof these non-B DNA structures, which
are likely to be essential componentsof genomes but somehow have been
disregarded in the past.

Genome Dynamics
11

Department of Genome Medicine

Genome Dynamics
12

Department of Genome Medicine
Project
LeaderYoshiaki Kikkawa Mammalian Genetics Project

Gene Discovery:
Phenotype- and gene-driven
approaches to discovering
disease-associated genes in mice
Seki, Y., Miyasaka, Y., Suzuki, S.,
Wada, K., Yasuda, S.P., Matsuoka,
K., Ohshiba, Y., Endo, K., Ishii, R., Shitara, H., Kitajiri, SI, Nakagata, N., Takebayashi, H., and Kikkawa Y. (2017)“A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear
hair cells.” PLoS One 12, e0183477.
Miyasaka, Y., Shitara, H., Suzuki, S.,
Yoshimoto, S., Seki, Y., Ohshiba, Y.,
Okumura, K., Taya, C., Tokano, H., Kitamura, K., Takada, T., Hibino, H., Shiroishi, T., Kominami, K., Yonekawa,H., and Kikkawa, Y. (2016) “Heterozygous mutation of Ush1g/Sans in micecauses early-onset progressive hearing loss, which is recovered by reconstituting the strain-specific mutation in
Cdh23.” Hum. Mol. Genet. 25, 20452059.
Kikkawa, Y., Miyasaka, Y. (2016) “Genetic modifiers of hearing loss in mice:
The case of phenotypic modification
in homozygous Cdh23ahl age-related
hearing loss.” Monogr. Hum. Genet.
20, 97–109.
Suzuki, S., Ishikawa, M., Ueda, T.,
Ohshiba, Y., Miyasaka, Y., Okumura,K., Yokohama, M., Taya, C., Matsuoka, K., and Kikkawa, Y. (2015) “Quantitative trait loci on chromosome 5 forsusceptibility to frequency-specific effects on hearing in DBA/2J mice.” Exp.
Anim. 64, 241-251.

Mouse disease models were contributed the identification of the causesof pathogenic mechanisms. Their demand will be increased because
generic factors and molecular mechanisms of the most genetic diseaseof human are still unknown in the most genetic disease. In particularly,
mouse disease models are important tools for discovering the genes thatare responsible for genetic diseases, allowing the processes that regulate
the onset of genetic diseases, and evaluation of the effectiveness of a
new drug; therefore, the establishment is essential study. We aim theestablishment of novel mouse disease models for phenotypic analysis ofgenetic diseases in human and identification of the causes of pathogenic
mechanisms by approaches of the forward and reverse genetics.

“We identify genes associated with humandiseases from mutant mice and develop new
mouse models for human diseases. ”

Wada, K., Matsushima, Y., Tada, T.,
Hasegawa, S., Obara, Y., Yoshizawa, Y., Takahashi, G., Hiai, H., Shimanuki, M., Suzuki, S., Saitou, J., Yamamoto, N., Ichikawa, M., Watanabe, K.,
and Kikkawa, Y. (2014) “Expression oftruncated PITX3 in the developing lens
leads to microphthalmia and aphakia
in mice.” PLoS One 9, e111432.

Mammalian Genetics
13

Department of Genome Medicine

Mammalian Genetics
14

Department of Genome Medicine
Project
LeaderFumihiko Yasui Viral Infectious Diseases ProjectControl of viral infectious diseases:
Virology, immunology, vaccinology
and therapy

Tokunaga Y., Osawa Y., Ohtsuki T.,
Hayashi Y., Yamaji K., Yamane D.,
Hara M., Munekata K., Tsukiyama-Kohara K., Hishima T., Kojima S., Kimura
K., Kohara M. (2017) Selective inhibitorof Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver
fibrosis i n m ouse m odel. Sci R ep. 7 ,325.
Sanada T., Hirata Y., Naito Y., Yamamoto N., Kikkawa Y., Ishida Y., Yamasaki C., Tateno C, Ochiya T, Kohara M.
(2016) Transmission of HBV DNA mediated by ceramide-triggered extracellular vesicles. Cell Mol Gastroenterol
Hepatol. 3, 272-283.
Yasui F, Itoh Y, Ikejiri A, Kitabatake M,
Sakaguchi N, Munekata K, Shichinohe
S, Hayashi Y, Ishigaki H, Nakayama
M, Sakoda Y, Kida H, Ogasawara K,
Kohara M. (2016) Sensitization withvaccinia virus encoding H5N1 hemagglutinin restores immune potential
against H5N1 influenza against H5N1
influenza virus. Sci Rep. 6, 37915.
Sanada T, Tsukiyama-Kohara K, Yamamoto N, Ezzikouri S, Benjelloun S,
Murakami S, Tanaka Y, Tateno C, Kohara M. (2016) Property of hepatitis B
virus replication in Tupaia belangeri
hepatocytes. Biochem Biophys Res
Commun. 469, 229-235.

Our project studies the virology, immunology, vaccinology and therapy ofincurable viral diseases. We currently focus on liver diseases, influenza
and dengue fever. However, the lack of suitable infection models in in
vitro and in vivo has hampered the clarification of pathogenesis by thesevirus infections. To overcome the problems, we have been developing
various animal models including transgenic mice, humanized mice withhuman liver cells, monkeys and tree shews. We also investigate theprecise mechanisms by which host factors regulate viral growth.

“We are studying to clarify the mechanisms
underlying development of severe acute inflammation and establishment of chronic infection byviruses through the development of suitable animal models that are capable of infecting viruses.”
Hepatitis

Influenza

Dengue fever

Identification of host factors
regulating virus growth.

Elucidation of the mechanisms
by which highly pathogenic Flu
causes severe pneumonia.

Development of suitableanimal models to study
vaccine efficacy andpathogenesis of dengue fever.

Elucidation of the mechanisms
underlying pathogenesis
caused by hepatitis virus
infection.
Development of therapeutic
vaccine and drug for chronic
HBV/HCV infection and otherliver diseases.

Development of novel vaccine
and therapeutic drug against
highly pathogenic Flu andseasonal Flu.

Yamamoto N, Sato Y, Munakata T, Kakuni M, Tateno C, Sanada T, Hirata Y,
Murakami S, Tanaka Y, Chayama K,
Hatakeyama H, Hyodo M, Harashima
H, Kohara M. (2016) Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments
for chronic HBV infection. J Hepatol.
64, 547-555.
Ohtsuki T., Kimura K., Tokunaga Y.,
Tsukiyama-Kohara K., Tateno C., Hayashi Y., Hishima T., Kohara M. (2015)
J. Virol. 90:300-307.

Viral Infectious Diseases
15

Development of novel vaccine
for all serotypes of DENV.

Department of Genome Medicine

Members

Michinori Kohara
Tsubasa Munakata
Yasuyuki Miyazaki
Daisuke Yamane
Takayuki Hishiki
Kenzaburo Yamaji
Naoki Yamamoto
Chun-Chieh Lin
Takahiro Ohtsuki
Keisuke Munekata
Yuko Tokunaga
Takahiro Sanada
Tomoko Honda

Viral Infectious Diseases
16Department of Genome Medicine
Project
LeaderSatoshi Koike Neurovirology ProjectProtecting the Central
Nervous System from
Infectious Diseases
Fujii K et al. (2013) “Transgenic mousemodel for the study of enterovirus
71 neuropathogenesis.” Proc. Natl.
Acad. Sci. USA., 110, 14753-14758.
Yamayoshi S et al. (2013) “Functional
Comparison of SCARB2 and PSGL1
as Receptors for Enterovirus 71.” J.
Vi-rol., 87, 3335-3347.
Yamayoshi S et al. (2012) “Human
SCARB2-dependent Infection by Coxsackievirus A7, A14, A16 and Enterovirus 71.” J. Virol., 86, 5686-5696.
Abe Y et al. (2012) “The Toll-like receptor 3-mediated antiviral response is important for protection against poliovirus
infection in poliovirus receptor transgenic mice.” J. Virol., 86, 185-194.
Yamayoshi S, Koike S (2011) “Identification of the Human SCARB2 Region That Is Important for Enterovirus
71 Binding and Infection.” J. Virol.,85, 4937-4936.
Yamayoshi S, et al. (2009) “Scavenger receptor B2 is a cellular receptor
for enterovirus 71.” Nature Medicine
15, 789-801.

“The development of vaccines and antiviraldrugs, and the use of experimental
models for the evaluation of these agentsare important for controlling viral
infections. We study the basic principles ofneurotropic enterovirus infection to develop
new technologies to control infectious diseases.”
Enterovirus 71 (EV71) belongs to human enterovirus species A of thegenus Enterovirus within the Picornaviridae family, and it is known to be
one of the causative agents of hand-foot-and-mouth disease (HFMD).
HFMD is considered to be a mild and self-limiting disease in general.
However, in some infants and young children, HFMD caused predominantly by EV71 can be complicated by neurological manifestations. Thus,
EV71 infection is a serious public health concern. Unfortunately, there is
still very little information concerning EV71 pathogenesis, and vaccines
or anti-EV71 drugs have yet to be developed.

EV71 antigens in the spinal cord of
SCARB2 tg mice

Neurovirology
17

Members

Ken Fujii

Kyosuke Kobayashi

Department of Genome Medicine

Research Topics

Neurovirology
18

Department of Genome Medicine
Project
LeaderTakachika Hiroi Allergy and Immunology Project

Allergy and Mucosal Immunology:
Investigating molecular mechanisms ofsublingual immunotherapy (SLIT) anddeveloping therapeutic biomarkers
for allergic diseases.

Nishimura, T., Kaminuma, O., Saeki, M., Kitamura, N., Matsuoka, K.,
Yonekawa, H., Mori, A., and Hiroi, T.
(2016) “Essential contribution of CD4+
T cells to antigen-induced nasal hyperresponsiveness in experimental allergic rhinitis.” PLOS ONE. 11, e0146686.
Yokoyama, S., Perera, PY., Terawaki, S., Watanabe, N., Kaminuma, O.,
Waldmann, TA., Hiroi, T., and Perera, LP. (2015) “Janus kinase inhibitor
tofacitinib shows potent efficacy in amouse model of autoimmune lymphoproliferative syndrome (ALPS).” J
Clin Immunol 35, 661-667.
Yokoyama, S., Takada, K., Hirasawa,
M., Perera, LP., and Hiroi, T. (2011)“Transgenic mice that overexpress human IL-15 in enterocytes recapitulate
both B and T cell-mediated pathologic manifestations of celiac disease.” J
Clin Immunol 31, 1038-1044.
Kaminuma, O., Kitamura, F., Miyatake,S., Yamaoka, K., Miyoshi, H., Inokuma,
S., Tatsumi, H., Nemoto, S., Kitamura,N., Mori, A., and Hiroi, T. (2009) “T-box
21 transcription factor is responsiblefor distorted TH2 differentiation in human peripheral CD4+ T cells.” J Allergy Clin Immunol 123, 813-823.
Yokoyama, S., Watanabe, N., Sato, N.,
Filkoski, L., Tanaka, T., Miyasaka, M.,
Waldmann, T.A., Hiroi, T., and Perera,PL. (2009) “Antibody-mediated blockade of IL-15 signaling reverses autoimmune intestinal damage in a mousemodel of celiac disease.” Proc. Natl
Acad Sci USA. 106, 15849-15854.

Japanese cedar pollen allergy is the major allergic disease in Japan, and the approximately 35% of Japanese people are affected. In recent years, sublingual
immunotherapy has been recognized as an effective
curative treatment for the allergic diseases.
However, the molecular mechanisms of mucosal tolerance still remain unclear. In our laboratory, we focus on the following subjects.

“We are developing new diagnostics
and treatments for allergies.”
1. Search for effective biomarkers of SLIT
・CNVs
・SNPs
・Epigenome
・Proteome, etc.

2. Elucidation of molecular mechanisms to induce
immunological tolerance by SLIT

Allergy and Immunology
19・iTregs
・Apoptosis
・CTLA-4・TGF-β・IL-10 etc.

Department of Genome Medicine

Allergy and Immunology
20Department of Genome Medicine
Project
LeaderMedical Research
Futoshi Shibasaki Molecular
Project

Translational Research for Cancer
and Infectious Diseases:
Basic to Applied Science

1. Endo F, et al.: Development of asimple and quick immun-chromato-graphy method for detection of anti-HPV-16/-18 antibodies. PLoS One.
2017;12(2):e0171314.
2. Sakurai A, et al.: Fluorescent immunochromatography for rapid and sensitive typing of seasonal influenza viruses. PLoS One. 2015;10(2):e0116715.

Recent discoveries of biomarkers and novel technologies have opened
the new aspects of the mechanisms and drug developments especially in cancer and infectious diseases. In basic science, whole genome
reads by next generation sequence (NGS) led to the paradigm shift fromsmall fragment to whole genome analysis. The detection of frequent
mutation in exon sequences in important kinases and other growth factor genes helps us to precise selection of new anti-cancer drugs (Precision Medicine) to ameliorate the prognosis even though the cancer
is extremely malignant. Our specific aims are to perform the basic science and be to develop the new findings to the translational research.

3. Nakano S, et al.: Immunochromato-graphic Detection of Serum
Anti-a-Galactosidase A Antibodies
in Fabry Patients after Enzyme Replacement Therapy. PLoS One.
2015;10(6):e0128351.
4. T. Hashimoto and F. Shibasaki.
Hypoxia-inducible factor as an angiogenic master switch. Front Pediatr.
2015;3:33.
5. Sakurai A, et al.: Multi-colored immunochromatography using nanobeads
for rapid and sensitive typing of seasonal influenza viruses. J Virol Methods. 2014;209:62-8.
6. Sakurai A, et al.: Broad-spectrum
detection of H5 subtype influenza A viruses with a new fluorescent immunochromatography system. PLoS One.
2013;8(11):e76753.
7. Nakano S, et al.: Developmentof a highly sensitive immuno-PCR
assay for the measurement of alpha-galactosidase A protein levels
in serum and plasma. PLoS One.
2013;8(11):e78588.
8. Li Chen, et al.: Mammalian Tumor
Suppressor Int6 Specifically Targets
HIF-2αTo Degradation by HypoxiaAnd pVHL- Independent Regulation. J.
Biol. Chem. 282. 12707-12716 (2007)
9. Chen L, et al.: Int6/eIF3e Silencing
Promotes Functional Blood Vessel Outgrowth and Enhances Wound Healingby Upregulating HIF2-a Expression.
Circulation 122: 910-919 (2010)

In basic Research, we focusing on the mechanisms of cancer angiogenesis and the drug development using siRNA, and on malignant
transformation and metastasis caused by cell fusion. The novel receptor
candidate for H5 influenza virus entrance into cell surface would be adrug target.
In clinical and translational research, we focus on the establishment ofplatform to perform “Precision Medicine” by Whole genome analysis
with next generation sequence in collaboration with Metropolitan Hospitals. For Private Public Partnership (3P), we have already establishedthe Bio-Consortium “Tokyo Biomarker Innovation Research Association” (TOBIRA).

Molecular Medical Research21

Department of Genome Medicine

Senior Research Scientist

Keisuke Oboki

Translational Research for Cancer

Genomics data brought by clinical specimens can now induce somemedical actions that have never been before. We aim to build valuable
research questions from clinical genomics data, and to progress basic
science and clinical medicine.

Endo F, et al.: PLoS One. 2017;12: e0171314.
Osawa Y, et al.:Inhibition of Cyclic Adenosine Monophosphate(cAMP)-response Element-binding Protein (CREB)-binding Protein(CBP)/β-Catenin Reduces Liver Fibrosis in Mice.
EBioMedicine. 2015; 2: 1751-8
With M. O,., T. H., and H. A.

Molecular Medical Research22Department of Dementia and Higher Brain Function
Project
LeaderMasato Hasegawa Dementia Research Project

Prion-like propagation of tau, α-synuclein
and TDP-43 in neurodegenerative diseases

Hasegawa M, Nonaka T, Masuda-Suzukake M. (2016) “α-Synuclein: Experimental Pathology “ Cold Spring Harb
Perspect Med. 6. pii: a024273.
Shimozawa A, Ono M, Takahara D, Tarutani A, Imura S, Masuda-Suzukake
M, Higuchi M, Yanai K, Hisanaga SI,
Hasegawa M . (2017) “Propagation ofpathological α-synuclein in marmoset
brain. Acta Neuropathol Commun.
5,12.
Tarutani A, Suzuki G, Shimozawa A,
Nonaka T, Akiyama H, Hisanaga S,
Hasegawa M . (2016) “The Effect ofFragmented Pathogenic α-Synuclein
Seeds on Prion-like Propagation.”
J Biol Chem 291, 18675-18688.
Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M . (2016) “Gainof-function profilin 1 mutations linked
to familial amyotrophic lateral sclerosis
cause seed-dependent intracellular
TDP-43 aggregation.” Hum Mol Genet
25, 1420-1433 .
Shimonaka S, Nonaka T, Suzuki G, Hisanaga S, Hasegawa M. (2016) “Templated Aggregation of TAR DNA-binding Protein of 43 kDa (TDP-43) bySeeding with TDP-43 Peptide Fibrils.”
J Biol Chem 291, 8896-8907 .

Neurodegenerative diseases are characterized by progressive degeneration of subsets of neurons and gliosis. Many of the diseases areaccompanied with intracellular amyloid-like protein pathologies, suchas tau in Alzheimer’s disease (AD), α-synuclein in dementia with Lewy
bodies (DLB) and TDP-43 in amyotrophic lateral sclerosis (ALS) andfrontotemporal dementias (FTLD). Importantly, the distributions andspread of these proteins are closely correlated with clinical presentationand disease progression. However, little attention had been given to thequestions of why these diseases are progressive, and why the pathologies spread to different brain regions during the course of the diseases.

Tau in AD

TDP-43 in ALS

α-synuclein in DLB“Emerging evidence indicates that intracellularamyloid-like proteins have prion-like properties andpropagate from cell to cell by converting normal
proteins into abnormal forms.
We are trying to elucidate the molecular mechanisms of‘prion-like propagation of these proteins.”
We have been investigating these intracellular abnormal proteins inbrains of patients, proteinchemically using LC/MS/MS, immuno-histochemically with specific antibodies and ultrastructuraly. And we foundthat all of these proteins are accumulated in brains of patients as fibrousor filamentous forms in hyperphosphorylated and partially ubiquitinatedstates.

Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda- Suzukake M, Tarutani A, Murayama S,
Saito Y, Arima K, Yoshida M, Akiyama
H, Robinson A, Mann D, Iwatsubo T,
Hasegawa M. (2016) “Biochemicalclassification of tauopathies by immunoblot, protein sequence and mass
spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau.” Acta
Neuropathol 131, 267-280 .

Schematic diagrams of human tau, α-synuclein and TDP-43.

Dementia Research23

Department of Dementia and Higher Brain Function

To investigate the molecular mechanisms of aggregation of these proteins, we established seed-induced
aggregation model which recapitulate the pathological protein aggregation in vitro, cultured cells and inbrains of animals (mouse and marmoset) and proposed a hypothesis “prion-like propagation of these
intracellular pathological proteins in brain”. These models are highly useful not only for clarifying the molecular mechanisms involved in the pathogenesis and progression of neurodegenerative diseases but
also for the development of disease modifying drugs and therapy.

Senior Research Scientist

Takashi Nonaka

Molecular mechanisms of cell-to-cell
propagation of aggregated proteins

Nonaka T et al. Phosphorylationof TAR DNA-binding Protein of
43 kDa (TDP-43) by TruncatedCasein Kinase 1δ Triggers Mislocalization and Accumulation of
TDP-43. J. Biol. Chem. 291: 54735483, 2016

I’m studying molecular mechanisms of cell-to-cell propagation of aggregated proteins (tau, α-synuclein and TDP-43) in neurodegenerative diseases. Also, I’m trying to make in vitro and in vivo models recapitulating
abnormal features found in cells of brains of patients using cultured cells
and mice. These models will contribute not only to a better understanding of the mechanisms involved in these diseases, but also to the development of novel therapeutic strategies.

Nonaka T et al. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell
Rep. 4: 124-134 , 2013
Nonaka T et al. Seeded aggregation and toxicity of alpha-synuclein
and tau: cellular models of neurodegenerative diseases. J. Biol.
Chem. 285: 34885-34898, 2010

Dementia Research24Department of Dementia and Higher Brain Function
Project
LeaderMinoru Saitoe Learning and Memory Project

Investigating the Molecular
Mechanisms that Generate Memoryencoding Neural Networks

Ueno K, Suzuki E, Naganos S, Ofusa
K, Horiuchi J, Saitoe M. (2017) “Coincident postsynaptic activity gates presynaptic dopamine release to induce
plasticity in Drosophila mushroom
bodies.” eLife, 6, e21076.
Hirano Y, Ihara K, Masuda T, Yamamoto T, Iwata I, Takahashi A, Awata H,
Nakamura N, Takakura M, Suzuki Y,
Horiuchi J, Okuno H, Saitoe M. (2016)“Shifting transcriptional machinery is
required for long-term memory maintenance and modification in Drosophila
mushroom bodies.” Nat Commun. 7,13471.
Matsuno M, Horiuchi J, Yuasa Y, Ofusa
K, Miyashita T, Masuda T, Saitoe M.
(2015) “Long-term memory formation in
Drosophila requires training-dependent glial transcription.” J Neurosci
35, 5557-5565.

Memories mold our personalities to make us who we are. Using powerful genetic tools, numbers of genes and neural substrates underlying memory-associated behaviors have been identified in Drosophila.
Given these scientific backgrounds, we have investigated when, where
and how identified memory-associated gene products function to produce memory-based behavior, and how the underlying mechanism ischanged in response to changes in physical condition such as aging.
In addition to behavioral genetic approach, we employ in vivo and exvivo imaging techniques to characterize physiological properties ofmemory-associated neural networks, and understand how memory-associated genes and neuromodulatory systems regulate function of these
networks; how sensory information is associated and how memory information is stored in neural substrates and recalled upon receiving test
stimuli.

“Combining of behavioral genetics and state-ofarts
imaging techniques, we aim to understand how
our brains store and retrieve memories.”

Yamazaki D, Horiuchi J, Ueno K, Ueno
T, Saeki S, Matsuno M, Naganos S,
Miyashita T, Hirano Y, Nishikawa H,
Taoka M, Yamauchi, Y, Isobe T, Honda Y, Kodama T, Masuda T, Saitoe
M. (2014) “Glial dysfunction causes
age-related memory impairment in
Drosophila.” Neuron 84, 753-763.
Hirano Y, Masuda T, Naganos S,
Matsuno M, Ueno K, Miyashita T,
Horiuchi J, Saitoe M. (2013) “Fasting
Launches CRTC to Facilitate Longterm Memory Formation in Drosophila.”
Science 339, 443-446.
Miyashita T, Oda Y, Horiuchi J, Yin JC,
Morimoto T, Saitoe M. (2012) “Mg2+block of Drosophila NMDA receptors
is required for long-term memory formation and CREB-dependent gene
expression.” Neuron 74, 887-898.

Flies perform olfactory conditioning
behavior, avoiding conditioned odor that
had been paired with electrical shock (left)
in the teaching machine (right)

Yamazaki D, Horiuchi J, Nakagami Y,
Nagano S, Tamura T, Saitoe M. (2007)“The Drosophila DC0 mutation suppresses age-related memory impairment without affecting lifespan.” Nat
Left, in vivo imaging of fixed fly under microscope is used to investigate activity of identified neuNeurosci 10, 478-484.
rons and network during sensory association (odor and shock), reinforcement, storage and retrieval. Right, using ex vivo imaging we attempt to make artificial memory in cultured brain, thereby
Tamura T, Chiang AS, Ito N, Liu HP,
elucidate the whole picture of the memory-associated networks.
Horiuchi J, Tully T, Saitoe M. (2003)“Aging specifically impairs amnesiac-dependent memory in Drosophila.”
Neuron 40, 1003-1011.

Learning and Memory25

Department of Dementia and Higher Brain Function

Current Research Topics
Encoding and decoding of memory: In Drosophila, themushroom body (MB) is a neural center for olfactory memory. As described by Hermann Ebbinghaus (1885), repetitive
olfactory conditioning with rest intervals, namely spaced
training, stabilizes labile short-term memory (STM) into robust long-term memory (LTM), which requires transcriptional
activity of CREB. Interestingly, STM and LTM are encoded Structure of MBs and their lobe
Left: MBs in the fly brain expressing GFP.
in different subset of MB neurons. While aversive STM is Right: Subdivision of MB lobes derived from each
encoded in gamma neurons, aversive LTM is encoded in al- type of MB neurons.
pha/beta neurons. We are interested in how such anatomical
shifting is occurred during stabilization of STM to LTM, functional relationship between STM and LTM.
Neuron-glia interactions: Recent research demonstrates
that neuron-glia communication is also important for
memory formation. We have identified a cell adhesion
molecule Klingon (Klg) that mediates neuron-glia communication required for LTM-based behavior. Currently,
we are studying how Klg-mediated neuron-glia interaction regulates memory acquisition, stabilization andretrieval. Also, we are interested in how this mechanism
is altered upon aging.

Klingon mediates neuron-glia interaction for LTM formation. A, B) Expression of Klingon (Klg) in the fly
brain. C) Expression of Klg in neurons. D) Expression of Klg in glial cells.
Spaced training increases Klg-mediated neuron-glia interaction, thereby induces Repo-dependent glialtranscription required for LTM.

Senior Research Scientist

Kohei Ueno

Exploring Physiological Systems
Underlying Learning and Memory
Neural plasticity is one of the important neurophysiological foundationsof memory formation. To investigate the biological system, we have developed isolated brain method. In the isolated brain, if we simultaneously
stimulate odor and somatosensory inputs, the neural activity in MB isenhanced for long-period. We believe that this physiological changes arebasis of fly memory. Recently, we found that the plastic change depends
dopaminesignaling, and the dopamine release for the plasticity requires MB activity. Thus, dopamine release is gated by postsynaptic neurons. We aretrying to uncover the mechanism of this mode of transmission and test
whether on-demand mode also works in other neuromodulatory systems
and in other animals.
If mushroom body neurons are activated by two inputs, namely odor
and somatosensory inputs, the activated mushroom body requires
dopamine release from dopaminergic neurons.

Learning and Memory26

Department of Dementia and Higher Brain Function
Project
LeaderYukio Nishimura Neural Prosthesis Project

Restoring Lost Function
After Neural Damage
Our research goal is to conceive innovative neruo-rehabilitation to restore lost functions after impairment of central nervous system, and totranslate our findings into clinical applications capable of improving thequality of life for individual with neural damages.
Kato K, Sasada S, Nishimura Y. (2016)“Flexible adaptation to an artificial
recurrent connection from muscle toperipheral nerve in man.” J Neurophysiol. 115, 978-991.
Sawada M, Kato K, Kunieda T,
Mikuni N, Miyamoto S, Onoe H, Isa T,
Nishimura Y (2015) “Function of thenucleus accumbens in motor control
during recovery after spinal cord
injury.” Science. 350, 98-101.
Sasada S, Kato K, Kadowaki S, Groiss
SJ, Ugawa Y, Komiyama T, Nishimura
Y. (2014) “Volitional walking via upper
limb muscle-controlled stimulation of
the lumbar locomotor center in man.” J
Neurosci. 34, 11131-11142.
Nishimura Y, Perlmutter SI, Eaton RW,
Fetz EE. (2013) “Spike-timing-dependent plasticity in primate corticospinal connections induced during freebehavior.” Neuron. 80, 1301-1309.

Nishimura Y, Perlmutter SI, Fetz EE.
(2013) “Restoration of upper limb
movement via artificial corticospinal
and musculospinal connections in amonkey with spinal cord injury.” Front
Neural Circuits. 7, 57.
Nishimura Y, Morichika Y, Isa T. (2009)“A subcortical oscillatory network contributes to recovery of hand dexterity
after spinal cord injury.” Brain. 132,709-721.
Nishimura Y, Onoe H, Morichika Y,
Perfiliev S, Tsukada H, Isa T. (2007“Time-dependent central compensatory mechanisms of finger dexterity
after spinal cord injury.” Science.
318, 1150-1155.

“Bridging Damaged Neural Pathways
using a Neural Interface.”
Regaining the function of an impaired
limb is highly desirable in individuals
experiencing paralysis. Functional lossof limb control in individuals with spinal
cord injury or stroke can be caused bytransection of descending and ascending pathways.those connects cortical tospinal network, although neural circuits
locate above and below the impaired site remains their function.

Translational Study
Artificial NeuralConnection

Neural Mechanism

Neuron 2013

Frotiers 2013

We are developing a neural interface which so-called “artificial neuronalconnection (ANC)”. The ANC bridges supra-spinal system and spinal
network beyond the lesion site to restore lost function. We are conducting clinical trials to assess effectiveness of ANC in restoring motor
function in paralyzed patients. We investigate neural changes that occur
during recovery.

Neural Prosthesis
27

J Neurosci 2014

Department of Dementia and Higher Brain Function

Neural Mechanisms of Functional Recovery
Using a large scale multichannel recording, pharmacologicalintervention, neuroanatomy, viral tools, computation andwhole brain imaging, we seek to uncover the neural mechanisms underlying the voluntary limb movement in intact
animals, as well as the processes that reestablish motor
functions after neural damages such as spinal cord injury
and stroke. We are also performing clinical studies to test theefficacy of the ANC in human patients.

Psychological Effect on Motor Control
Mental Effort

Mesolimbic

Motor

Science. 2007, Brain 2009

Emotional states influence how we perform
motor activities and how we perceive errors.
Depression impedes and motivation enhances
functional recovery after neuronal damage. However, the neuronal substrate underlying such
psychological effects on functional recovery
remains unclear. We investigate the neural substrate underlying such psychological effects on
motor performance in human and animal modelof neural damages.

Motor Control
PLoS ONE 2011, Science. 2015

Members
Yukio Nishimura Yoshihisa Nakayama

Toshiki Tazoe

Osamu Yokoyama

Nobuya Sano

Miki Kaneshige

Hiroaki Ishida
Kei Obara

Michiaki Suzuki
Yu Shimada

Neural Prosthesis
28

Department of Dementia and Higher Brain Function

Unit Leader

Makoto Hashimoto Parkinson’s disease Unit

Protection ofneurodegenerative diseases
Research description

Hashimoto M, Ho G, Sugama S,
Takamatsu
Y,
Shimizu
Y,
Takenouchi T, Waragai M, Masliah
E. Evolvability of Amyloidogenic
Proteinsin
Human
Brain. J
Alzheimers Dis. 2018, 62:73-83.
Waragai M, Ho G, Takamatsu Y, Sekiyama K, Sugama S, Takenouchi T,
Masliah E, Hashimoto M. Importanceof adiponectin activity in the Pathogenesis of Alzheimer’s Disease. Ann Clin
Transl Neurol. 2017,4:591-600.
Takamatsu Y, Ho G, Koike W, Sugama
S, Takenouchi T, Waragai M, Wei J,
Sekiyama K, Hashimoto M. Combined
immunotherapy with “anti-insulin resistance” therapy as a novel therapeuticstrategy against neurodegenerative
diseases. NPJ Parkinsons Dis. 2017,
3: 4.
Takamatsu Y, Koike W, Takenouchi T,
Sugama S, Wei J, Waragai M, Sekiyama K, Hashimoto M. Protection against
neurodegenerative disease on Earthand in space. NPJ Microgravity 2016,
2: 16013.
Waragai M, Adame A, Trinh I, Sekiyama K, Takamatsu Y, Une K, Masliah
E, Hashimoto M. Possible Involvementof Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer’s Disease. J Alzheimers Dis.
2016, 52:1453-1459.

The number of patients with age-associated neurodegenerative diseases, such as
Alzheimer’s disease (AD) and Parkinson’s
disease (PD), is rapidly increasing worldwide. Consequently, huge costs for medical treatment and nursing care for thesepatients have become a serious socioeconomic dilemma. Nonetheless, extensive
studies of amyloid immunotherapy in AD
have been so far unsatisfactory. Thus, thedevelopment of an effective disease-modifying therapy is the highest priority in neurodegenerative disease research.

In our laboratory, we seek to exploit a mechanism-based diseasemodifying strategy for a-synucleinopathies, such as PD and de-mentia
with Lewy bodies. In this context, we have a particular interest in the
suppressive effect of adiponectin (APN) on neurodegeneration (Fig.1).
We will also attempt to identify new molecules that could be useful forthe prevention of neurodegenerative diseases. For such purposes, we
cur-rently perform the Drosophila molecular genetics (Fig.2) inaddition to cell biological and transgenic mice studies. Apparently, theresults will be applicable to other diseases, including AD and
Huntington’s disease.

Members
Yoshiki Takamatsu
Masaaki Waragai
Hiromu Sugino
Yuka Shimizu

Sekiyama K, Takamatsu Y, Koike W,
Waragai M, Takenouchi T, Sugama S,
Hashimoto M. Insight into the Dissociation of Behavior from Histology in Synucleinopathies and in Related Neurodegenerative Diseases. J Alzheimers
Dis. 2016, 52:831-841.

Parkinson’s disease
29

Fig. 1 APN ameliorates negeneration in
mice.

Fig. 2 Drosophila molecular genetics.

Department of Dementia and Higher Brain Function

Unit Leader

Toshiki Uchihara Structural Neuropathology Unit

Correlating Clinical Diagnoses with Brain
Lesion Progression in Alzheimer's andParkinson's Diseases

Uchihara T. (2017) “An order in Lewy
body disorders:” Neuropathology.
37, 129-149.
Uchihara T, Giasson BI. (2016) “Propagation of alpha-synuclein pathology: questions from experimental andhuman brain studies.” Acta Neuropathol. 131(1):49-73.

Questions : AD, PD-selective vulnerability?
Challenge : Expand molecule-oriented view
		 by tracing human brain lesions along connections.
Strategy : Seamless tracing from molecule to lesion distribution
by integrating small parts into upper hierarchy.

“Identifying the earliest lesions andcorrelating them with clinical indices forearly and specific diagnoses.”

Takahashi M, Ikemura M, Oka
T,Uchihara T, et al. (2015)“Quantitative correlation between
cardiac
MIBG
uptakeandremaining axons in the cardiac
sympathetic nerve in Lewy bodydisease.” J Neurol Neurosurg
Psychiatry. 86, 939-944.
Uchihara T, Endo K, Kondo H, et al.
(2016) “Tau pathology in aged cynomolgus monkey.” Acta NeuropatholComm. 4, 118.
Duyckaerts C, Braak E, Uchihara T.
(2015) “PART is part of AD.” Acta
Neuropathol. 129, 749-756.
Tatsumi S, Uchihara T, et al. (2014)“Ultrastructural differences in pretangles between AD and CBD.”
Acta Neuropathol Comm. 2, 161.
Hara M, Hirokawa K, Kamei S, Uchihara T. (2013) “Isoform transition fromfour-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology.”
Acta Neuropathol. 125, 565-579.
Uematsu M, Adachi E, Nakamura
A, Tsuchiya K, Uchihara T. (2012)“Atomic identification of fluorescent Q-Dots on tau-positive fibrils in
3D-reconstructed Pick bodies.” Am J
Pathol. 180, 1394-1397.

Structural Neuropathology
30Department of Brain Development and Neural Regeneration
Project
LeaderHiroshi Sakuma Developmental
Neuroimmunology Project

Towards a Better Understanding of
Neuro-immune Interactionsin the Developing Brain

Nakahara E, Sakuma H, Kimura-Kuroda J, Shimizu T, Okumura A, Hayashi
M. (2015) “A diagnostic approach for
identifying anti-neuronal antibodies
in children with suspected autoimmune encephalitis.” J Neuroimmunol
285, 150-155.
Sakuma H, Tanuma N, Kuki I, Takahashi Y, Shiomi M, Hayashi M. (2015)“Intrathecal overproduction of proinflammatory cytokines and chemokines
in febrile infection-related refractorystatus epilepticus.” J Neurol Neurosurg Psychiatr 86, 820-822.
Noto D & Sakuma H (double first authors), Takahashi K, Saika R, Saga R,
Yamada M, Yamamura T, Miyake S.
(2014) “Development of a Culture System to Induce Microglia-like Cells from
Haematopoietic Cells.” Neuropathol
Appl Neurobiol 40, 697-713.
Hachiya Y, Uruha A, Kasai-Yoshida E,
Shimoda K, Satoh-Shirai I, Kumada S,
Kurihara E, Suzuki K, Ohba A, Hamano SI, Sakuma H. (2013) “Rituximab
ameliorates anti-N-methyl-D-aspartate
receptor encephalitis by removal ofshort-lived plasmablasts.” J Neuroimmunol 265, 128–130

Our research focuses on the role of immune system in the developing brain.
Immune and inflammatory responses
not only combat pathogens but also
play a variety of physiological roles in
the central nervous system.
Microglia are brain-resident immune
cells and play multiple roles in the protection from pathogens and the clearance of debris. In addition, recent
studies have shed light on unexpected functions of microglia in thephysiological condition. For example, microglia actively participate in
the brain development by modulating synapses.

“We are investigating the mechanisms bywhich microglia maintain homeostasis in
the developing brain.”
Our main research areas include:
1)
2)
3)
4)
5)

Development and differentiation of microglia
Neuron-microglia interaction
In-vitro differentiated myeloid cells for cell therapy
Autoantibodies associated with neurological diseases
New biomarkers for pediatric immune-mediated neurological diseases

Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, Sugai
K, Sasaki M. (2010) “Acute encephalitis with refractory, repetitive partial
seizures (AERRPS): a peculiar form ofchildhood encephalitis.” Acta Neurol
Scand. 121, 251-256.

Developmental Neuroimmunology
31

Department of Brain Development and Neural Regeneration

Developmental Neuroimmunology
32Department of Brain Development and Neural Regeneration
Project
LeaderKanato Yamagata Synaptic Plasticity Project

Synaptic Plasticity and Brain Diseases:
Elucidating the mechanism fordevelopmental epilepsy,
intellectual disability and autism

Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H. Non-clustered protocadherin. Cell Adh Migr. 5(2):97-105,
2011.
Shimada T, Takemiya T, Sugiura H,
Yamagata K. Role of Inflammatory mediators in the pathogenesis of epilepsy. Mediators Inflamm. 2014:901902,
2014.
Yasuda S, Sugiura H, Katsurabayashi
S, Shimada T, Tanaka H, Takasaki K,
Iwasaki K, Kobayashi T, Hino O, Yamagata K. Activation of Rheb, but notof mTORC1, impairs spine synapse
morphogenesis in tuberous sclerosis
complex. Sci Rep. 4:5155, 2014.
Sugiura H, Yasuda S, Katsurabayashi
S, Kawano H, Endo K, Takasaki K, Iwasaki K, Ichikawa M, Kobayashi T, Hino
O, Yamagata K. Rheb activation disrupts spine synapse formation throughaccumulation of syntenin in tuberous
sclerosis complex. Nat Commun.
6:6842, 2015.
Masui K, Tanaka K, Ikegami S, Villa
GR, Yang H, Yong WH, Cloughesy
TF, Yamagata K, Arai N, Cavenee
WK, Mischel PS. Glucose-dependentacetylation of Rictor promotes targetedcancer therapy resistance. Proc Natl
Acad Sci U S A. 112(30):9406-11,
2015.
Shimada T, Yoshida T, Yamagata K.
Neuritin Mediates Activity-Dependent Axonal Branch Formation inPart via FGF Signaling. J Neurosci.
36(16):4534-48, 2016.

Our project examines the molecular basis of activity-dependent synaptic
plasticity. In particular, we have cloned a set of immediate early genes(IEGs) that are rapidly transcribed in neurons involved in information
processing, and that are essential for long term memory. IEG proteinscan directly modify synapses and provide insight into
cellular mechanisms that support synaptic plasticity.
Furthermore, these IEG products have been shown to
be involved in developmental brain disorders, including refractory epilepsy, intellectual disability and/or
autism.

“We have clarified mechanisms ofrefractory epilepsy, intellectual
disability and/or autism caused by
impaired synaptic plasticity.
Based on the novel mechanisms
we found, we are trying to findnew treatments for developmental
brain disorders.”

For example, COX-2 and mPGES-1 are prostaglandin synthases andexacerbate neuronal cell death after seizures, leading to intractable epilepsy. Arcadlin is a protocadherin and induces spine shrinkages after
seizures, resulting in developmental delay or amnesia. Rheb regulates
excitatory synapse formation via syntenin.
Its constitutive activation causes TSC (tuberous sclerosis complex),
which is accompanied by epilepsy, mental retardation and autism. Finally, neuritin is a secreted or membrane-anchored protein and induces
neurite branching. It may be involved in temporal lobe epilepsy. Thus,
rapid de novo transcription provides novel insights into the cellular andneural network basis of behavioral plasticity.
We will also explore the possibility thatthese IEG products could be therapeutic targets for developmental disorders.
We are making genetic mouse models
of developmental disorders and are
testing several drug inhibitors against
IEGs for such diseases.

Synaptic Plasticity
33

Department of Brain Development and Neural Regeneration

Synaptic Plasticity
34

Department of Brain Development and Neural Regeneration
Project
LeaderHaruo Okado Neural Development Project

Brain Development and Maintenance:

Hirai S., Hotta K., Kubo Y., Nishino A.,
Okabe S., Okamura Y., and Okado H.
(2017) “AMPA glutamate receptors
are required for sensory-organ formation and morphogenesis in the basal
chordate.” Proc. Natl. Acad. Sci.
USA. 114, 3939-3944.

Various factors control differentiation of neural stem cells and survival of
the resulting neurons and aberrancy of these processes are involved in
the incidences of intellectual disability and age-related brain disorders
and brain tumors .
We aim to elucidate the mechanisms of the development and maintenance of brain functions and ultimately to develop methods for prevention and treatment of intractable cranial nerve diseases.

Nakajima K., Hirai S., Morio T., andOkado H. (2015) “Benzodiazepines
induce sequelae in immature micewith inflammation-induced status epilepticus.” Epilepsy & Behavior 52,
180-186.
Ohtaka-Maruyama C., Hirai S., Miwa
A., Heng JI., Shitara H., Ishii R., TayaC., Kawano H., Kasai M., Nakajima K.,
and Okado H. (2013) “RP58 regulates
the multipolar-bipolar transition of newborn neurons in the developing cerebral cortex.” Cell Rep. 3, 458-471.
Hirai S., Miwa A., Ohtaka-MaruyamaC., Kasai M., Okabe S., Hata Y., andOkado H. (2012) “RP58 controls neuron and astrocyte differentiation by
downregulating the expression of Id14 genes in the developing cortex.”
EMBO J. 31, 1190-1202.

Various gene-targeted mice

“We are studying the effects of various
genetic and environmental factors on themolecular mechanisms of brain
development and maintenance,with the ultimate goal of developing newtreatments mental diseases.”

Ohtaka-Maruyama C., Hirai S., Miwa
A., Takahashi A., and Okado H. (2012)“The 5’-flanking region of the RP58
coding sequence shows prominentpromoter activity in multipolar cells inthe sub- ventricular zone during corticogenesis.” Neuroscience 201, 6784.
Okado H., Ohtaka-Maruyama C., Sugitani Y., Fukuda Y., Ishida R., Hirai S.,
Miwa A., Takahashi A., Aoki K., Mochida K., Suzuki O., Honda T., NakajimaK., Ogawa M., Terashima T., Matsuda
J., Kawano H., and Kasai M. (2009)“Transcriptional repressor RP58 is
crucial for cell-division patterning andneuronal survival in the developing
cortex.” Dev. Biol. 331, 140-151.

Neural Development
35

in utero electroporation

Laboratory Members

Department of Brain Development and Neural Regeneration

Shinobu Hirai

Tomoko Tanaka

Yoshie Matsumoto

Seiji Kanzaki

Tomoko Fukuoka

Neural Development
36

Department of Brain Development and Neural Regeneration
Project
LeaderNobuaki Maeda Neural Network ProjectMechanisms of Neural Network Formation:
Neuronal migration and synapse formation

Ishii, M. and Maeda, N. (2008) “Oversulfated chondroitin sulfate plays critical roles in the neuronal migration in
the cerebral cortex.” J Biol Chem 283,
32610-32620.
Nishimura, K., Ishii, M., Kuraoka, M.,
Kamimura, K. and Maeda, N. (2010)“Opposing functions of chondroitin sulfate and heparan sulfate during earlyneuronal polarization.” Neuroscience
169, 1535-1547.
Kamimura, K., Maeda, N. and Nakato,
H. (2011) “In vivo manipulation of heparan sulfate structure and its effect on
Drosophila development.” Glycobiology 21, 607-618.
Kamimura, K., Ueno, K., Nakagawa,J., Hamada, R., Saitoe, M. and Maeda,
N. (2013) “Perlecan regulates bidirectional Wnt signaling at the Drosophila
neuromuscular junction.” J Cell Biol
200, 219-233.
Maeda, N. (2015) “Proteoglycans andneuronal migration in the cerebral cortex during development and disease.”
Front Neurosci 9, 98.

In the developing nervous system, diverse types of neurons are generated from neural progenitors, and migrate to specific destinations. Then,
neurons extend axons toward specific target cells and form synapses
on them. These developmental processes require complex cell-cell andcell-extracellular matrix interactions. The extracellular matrix is an intricate network of molecules composed of proteoglycans, hyaluronan, andfibrous glycoproteins, which fill up the extracellular space. In the meshwork of extracellular matrix, various signal molecules such as growth
factors and chemokines are stored.

“We are interested in the roles of theextracellular matrix in neuronal network
formation. In the developing nervous system,
the extracellular matrix plays a dynamic role
in regulating the behaviors of diverse types ofneurons.”
To explore the functions of extracellular matrix in the developing neural networks, we adopted two animal models: mouse cerebrum andDrosophila neuromuscular junction (NMJ). Using in utero eletroporationand live cell imaging techniques, we are investigating the migration of
excitatory neurons in the mouse neocortex. Drosophila NMJ is a readily accessible model of excitatory synapses, which resemble the glutamatergic synapses of vertebrate central nervous system. By using thesophisticated genetic tools of Drosophila, it is possible to unravel thecomplicated roles of extracellular matrix in the synapse formation.

Ohtaka-Maruyama, C. et al. (2013)“RP58 regulates the multipolar-bipolartransition of newborn neurons in thedeveloping cerebral cortex.” Cell Rep
3, 458-471.
Ohtaka-Maruyama, C. and Okado, H.
(2015) “Molecular pathways underlying projection neuron production andmigration during cerebral cortical development.” Front Neurosci. 9, 447.

Neural Network
37

Department of Brain Development and Neural Regeneration

Senior Research Scientist

Chiaki Ohtaka-Maruyama

The Role of Subplate Neurons in theDevelopment and Evolution of the Neocortex

How does mammalian neocortex acquire a unique six-layered structurethat is a structural basis for the complex neural circuits, the remarkableproduct of evolution? To approach this question, we are focusing on the
subplate (SP) neurons in the developing neocortex: one of the first bornand matured cortical neurons that disappear postnatally. Recently, we
found that SP neurons play critical roles in radial neuronal migration via
direct interaction with migrating young neurons. Moreover, SP layer is rich in extracellular matrix,
which may play important regulatory roles in the neuronal polarization. Functional elucidation of SPlayer should lead to the better understanding of brain development and evolution.

Neural Network
38

Department of Psychiatry and Behavioral Sciences
Project
LeaderAtsushi Nishida Mental Health Promotion Project

No health without Mental Health:Mental Health promotion as the first priority in our society

Nakanishi M, Niimura J, Yamasaki S,
Nishida A (2017) “Death of dementia inpatients in Japanese psychiatric hospitals accounts for one-fifth ofdischarge destination in national datafrom 1996 to 2014” J Alzheimers Dis.
56, 817-824.
Nakanishi M, Nakashima T, Shindo Y,
Niimura J, Nishida A (2016) “Japanesecare location and medical proceduresfor people with dementia in the lastmonth of life.” J Alzheimers Dis. 51,
747-755.
Ando S, Koike S, Shimodera S, Fujito
R, Sawada K, Terao T, Furukawa TA,
Sasaki T, Inoue S, Asukai N, Okazaki
Y, *Nishida A. “Lithium levels in tap
water and the mental health problemsof adolescents: an individual levelcross-sectional survey.”
J Clin Psychiatry. 78, e252-e256.

While life in big cities, microcosms of today’s stressful societies, is afull of risk factors for mental health, interpersonal bonds that support
individuals are increasingly weakening. Hence, multifaceted research ofmental health promotion via clinical medicine and sociomedical methodologies needs to be promoted.
Mental Health Promotion Project engages in promoting mental well-being in big cities through: empirical findings from large-scale birth cohort
studies conducted in partnership with municipalities of Tokyo which isexperiencing increasingly aging population and low birthrate; and developing programs in collaboration with clinical forefront of care.

“We are trying to elucidate preventive factors tomental health problems and enhancing factors tomental well-being, and to improve care for people
living in the community and their families.”
Our goals are as follows: 1) Elucidate preventive factors to mental healthproblems and enhancing factors to mental well-being in adolescence.
2) Improve care for people with dementia living in the community andtheir families. 3) Develop transition support program connecting acutephase hospital treatment and post-discharge outpatient treatment.

Yamasaki S, Ando S, Koike S, Usami
S, Endo K, French P, Sasaki T, Furukawa TA, Hasegawa-Hiraiwa M, Kasai
K, Nishida A (2016) “Dissociation mediates the relationship between peer
victimization and hallucinatory experiences among early adolescents.”
Schizophr Res Cogn. 4, 18–23.

● Increase of dementia people: Est. number in 2025 is 7 million(MHLW, 2014)● The biggest cause of health damage among young people ismental illnesses and suicide (Patton, Lancet, 2009)

Mental Health Promotion
39

Department of Psychiatry and Behavioral Sciences

Mental Health Promotion
40Department of Psychiatry and Behavioral Sciences
Project
LeaderMakoto Arai Schizophrenia Research Project

Identifying Biomarkers of Schizophrenia

Itokawa, M., Miyashita, M., Arai, M.,
Dan, T., Takahashi, K., Tokunaga, T.,
Ishimoto, K., Toriumi, K., Ichikawa, T.,
Horiuchi, Y., Kobori, A., Usami, S., Yoshikawa, T., Amano, N., Washizuka, S.,
Okazaki, Y., Miyata, T. (2017) “Pyridoxamine, A Novel Treatment For Schizophrenia With Enhanced CarbonylStress.” Psychiatry Clin Neurosci. inpress
Miyashita, M., Watanabe, T., Ichikawa,T., Toriumi, K., Horiuchi, Y., Kobori, A.,
Kushima, I., Hashimoto, R., Fukumoto, M., Koike, S., Ujike, H., Arinami, T.,
Tatebayashi, Y., Kasai, K., Takeda, M.,
Ozaki, N., Okazaki, Y., Yoshikawa, T.,
Amano, N., Washizuka, S., Yamamoto,H., Miyata, T., Itokawa, M., Yamamoto, Y., Arai, M. (2016) “The regulationof soluble receptor for AGEs contributes to carbonyl stress in schizophrenia.” Biochem Biophys Res Commun. 479, 447-452.
Arai, M., Miyashita, M., Kobori, A., Toriumi, K., Horiuchi, Y., Hatakeyama, S.,
Itokawa, M. (2014) “Carbonyl stressand schizophrenia.” Psychiatry Clin
Neurosci. 68, 655-665.
Miyashita, M., Arai, M., Kobori, A.,
Ichikawa, T., Toriumi, K., Niizato, K.,
Oshima, K., Okazaki, Y., Yoshikawa,T., Amano, N., Miyata, T., Itokawa, M.
(2014) “Clinical Features of Schizophrenia With Enhanced Carbonyl Stress.”
Schizophr Bull. 40, 1040-1046.

The profiling of the peripheral metabolic system is a viable schizophrenia research strategy that can lead to earlier diagnostic methods, elucidation of its molecular mechanisms, and novel forms of treatment andprophylaxis.
We focus on 1) developing individualized medicine for treating schizophrenia, 2) investigating factors involved in disease onset, and 3) understanding the molecular pathology by using biomarkers to overcome thebarrier of heterogeneity. Our research outcomes will be applied to drug
development by establishing a new biomarker-based field of researchin molecular psychiatry. Data obtained from metabolomics, genomics,
induced pluripotent stem (iPS) cell models, animal models, post-mortem
brain analyses, neuropsychology, and genetic counseling research will
be consolidated to elucidate the genetic and environmental factors relevant to psychiatric disorders such as schizophrenia.

“Identifying biomarkers will allow us to classify
schizophrenia into different types, and aid in
earlier diagnoses and better treatments, leading to
improvements in patients’ quality of life.”
Schizophrenia

Arai, M., Nihonmatsu-Kikuchi, N., Itokawa, M., Rabbani, N., Thornalley, PJ.
(2014) “Measurement of glyoxalase activities.” Biochem Soc Trans. 42, 491494.
Miyashita, M., Arai, M., Yuzawa, H.,
Niizato, K., Oshima, K., Kushima, I.,
Hashimoto, R., Fukumoto, M., Koike,S., Toyota, T., Ujike, H., Arinami, T., Kasai, K., Takeda, M., Ozaki, N., Okazaki, Y., Yoshikawa, T., Amano, N., Miyata, T., Itokawa, M. (2014) “Replicationof enhanced carbonyl stress in a subpopulation of schizophrenia.” Psychiatry Clin Neurosci. 68, 83-84.
Arai, M., Koike, S., Oshima, N., Takizawa, R., Araki, T., Miyashita, M., Nishida, A., Miyata, T., Kasai, K., Itokawa,M. (2011) “Idiopathic carbonyl stressin a drug-naive case of at-risk mental
state.” Psychiatry Clin Neurosci. 65,
606-607.
Arai, M., Yuzawa, H., Nohara, I., Ohnishi, T., Obata, N., Iwayama, Y., Haga,
S., Toyota, T., Ujike, H., Arai, M., Ichikawa, T., Nishida, A., Tanaka, Y., Furukawa, A., Aikawa, Y., Kuroda, O., Niizato, K., Izawa, R., Nakamura, K., Mori,N., Matsuzawa, D., Hashimoto, K., Iyo,
M., Sora, I., Matsushita, M., Okazaki, Y.,
Yoshikawa, T., Miyata, T., Itokawa, M.
(2010) “Enhanced Carbonyl Stress in a
Subpopulation of Schizophrenia.” ArchGen Psychiatry. 67, 589-597.

This biomarker-based approach is anticipated to become an innovativeand creative strategy for elucidating the metabolic system of schizophrenia disease expression independently of conventional pathologicalhypotheses. Verification in cellular and animal models can shed lighton the molecular mechanisms underlying the utility of naturally-derived
substances, and is expected to lead to the future development of muchsafer treatments and prophylactic methods.

Schizophrenia Research41

Department of Psychiatry and Behavioral Sciences

Schizophrenia Research42Department of Psychiatry and Behavioral Sciences
Project
Leader

Disorders
Yoshitaka Tatebayashi Affective
Research Project

Our Goal is to Decipher the
Neurobiological Bases ofAffective Disorders.
Bauer M, (64 co-authors), Tatebayashi
Y et al. (2014) “Relationship between
sunlight and the age of onset of bipolar disorder: an international multisite
study.” J Affect Disord 167, 104-111.
Nihonmatsu-Kikuchi N, Hayashi Y, Yu
XJ, Tatebayashi Y. (2013) “Depression
and Alzheimer’s disease: novel postmortem brain studies reveal a possible
common mechanism.” J Alzheimers
Dis 37, 11-21.
Tatebayashi Y, Nihonmatsu-Kikuchi N,
Hayashi Y, Yu XJ, Soma M, Ikeda K.
(2012) “Abnormal fatty acid composition in the frontopolar cortex of patientswith affective disorders.” Transl
Psy-chiatry 2, e204.

Major depressive disorder (MDD) and bipolar disorder (BD), collectively known as affective disorders, are essentially relapsing and remitting
disorders of affect with nearly full recovery between episodes. We use
human postmortem brains of these disorders and animal and cell culture models to identify the processes in which stress or aging causeschanges in brain to induce these disorders. A major focus of our work is
stress-induced or age-related changes in cellular structure, especiallythat of oligodendrocyte lineage cells and lipid, within the brain’s mood
circuitry. We are also interested in the biological relationship between
affective disorders and dementias such as Alzheimer’s disease.

“Our human postmortem brain studies reveal
oligodendroglial reductions and myelindependent
fatty acid abnormalities in thefrontopolar cortex in affective disorders.”

Hayashi Y, Nihonmatsu-Kikuchi N, Hisanaga S, Yu XJ, Tatebayashi Y. (2012)“Neuropathological similarities anddifferences between schizophrenia
and bipolar disorder: a flow cytometricpostmortem brain study.” PLoS One 7,
e33019.
Hayashi Y, Nihonmatsu-Kikuchi N,
Yu XJ, Ishimoto K, Hisanaga SI, Tatebayashi Y. (2011) “A novel, rapid,
quantitative cell-counting method reveals oligodendroglial reduction in thefrontopolar cortex in major depressive
disorder.” Mol Psychiatry 16,1155-1158.

The exact functions of the human frontopolar cortex (BA10) remain enigmatic. Given that the BA10 is thought to be the most evolutionarily recent
expansion of the primate prefrontal cortex, its function may uniquely reflect human adaptations in the context of selecting and updating modelsof reward contingency in dynamic environments. As adulthood corticalmyelination is an essential process for the establishment of efficient neuronal signaling networks, any abnormalities in this process may haveimportant roles in the pathophysiology of affective disorders.

Affective Disorders Research
43Department of Psychiatry and Behavioral Sciences

Affective Disorders Research
44

Department of Psychiatry and Behavioral Sciences
Project
LeaderMakoto Honda Sleep Disorders Project

Narcolepsy and Hypersomnia:

Find the causes to develop better treatments

Miyagawa T, -, Tokunaga K, Honda
M. (2011) Abnormally low serum acylcarnitine levels in narcolepsy patients.
Sleep 34, 349-353.
Miyagawa T,--, Honda M. (2013) Effects of oral L- carnitine administrationin narcolepsy patients: a randomized, double-blind, cross-over andplacebo-controlled trial. PLoS ONE
8, e53707.
Honda M, --, Mignot E.(2009) IGFBP3
colocalizes with and regulates hypocretin(orexin). PLoS ONE 4, e4254.
Tanaka S, Honda Y, Inoue Y, Honda
M. (2006) Detection of autoantibodies
against hypocretin, hcrtrl, and hcrtr2 innarcolepsy: anti-Hcrt system antibody
in narcolepsy. Sleep 29, 633-638.
Tanaka S, Honda M (2010) IgG abnormality in narcolepsy and idio-pathic hypersomnia. PLoS ONE 5, e955.
Miyagawa T,-,Honda M, Tokunaga K(2015) New susceptibility variants tonarcolepsy identified in HLA class IIregion. Hum Mol Genet 24, 891-8.

Narcolepsy is a sleep disorder with abnormal intrinsic sleep-wake regulation, resulting in unique symptoms including frequent lapses into
sleep, nocturnal sleep instability and REM sleep related manifestations
such as cataplexy (abrupt loss of muscle tone triggered by emotion),sleep paralysis and hypnagogic hallucination.
Narcolepsy is associated with a deficiency of wake-promoting orexin/
hypocretin producing neurons localized in hypothalamus, and virtually
all the patients carry human leukocyte antigen (HLA)-DQB1*06:02.

“We are trying to solve the mystery of narcolepsy:
Listen to the patients, get the whole picture, andimprove their lives.”

Narcolepsy is associated with a variety of physical and psychiatric comorbid conditions. Since appropriate wakefulness is essential for higher
brain functions, abnormal sleep-wake regulation can lead to various associated features. Despite the progress in sleep research fields, we currently have inadequate symptom-based-treatments for sleep disorders,
including narcolepsy. We are trying to elucidate the pathophysiology ofnarcolepsy with multifaceted problems to improve the QOL of hypersomnia patients.

Research Strategy

Toyoda H, -, Honda M (2010) Anti-tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy. Sleep
33, 875-878.
Tanaka S,-, Kodama T. (2017) Anti-tribbles pseudokinase 2 (TRIB2)-immunization modulate Hypocretin/Orexin
neuronal functions. Sleep 40:zsw036.
Honda M, Arai T,-, Mignot E. (2009)
Absence of ubiquitinated inclusions in
hypocretin neurons of narcolepsy patients. Neurology 73, 511-517.
Miyata R, -, Honda M.(2017) Steroid
therapy ameliorated cataplexy in threechildren with recent-onset of narcolepsy. Sleep Med 29, 86-87.

Sleep Disorders45

Department of Psychiatry and Behavioral Sciences
Research Interests

Hypothalamus works as a center for sleep-wake switch in coordination with the integrated informationfrom the body. Among them, we have particular interests in immune and metabolic status, which can be
the key to understand altered sleep-wake regulation in narcolepsy.

1. HLA association and immune abnormality

In addition to the tight association with HLA, narcolepsy is also associated with T cell receptor (TCR) alpha locus, indicating the HLA-TCR mediated immunological alterations. Both genetic and environmental
factors are implicated in narcolepsy predisposition. We have reported the altered immune status in narcolepsy, but so far could not confirm the leading hypothesis that orexin neurons are destructed by direct
autoimmune attacks. Immune mechanisms other than autoimmunity might lead to stop producing orexin
neuropeptide.

2. Metabolic aspect of narcolepsy and related hypersomnia

Through genome-wide association studies (GWAS), we have identified novel narcolepsy (and other hypersomnia) related genes. They are key enzymes located in the pathway of fatty acid metabolism. We
confirmed their functional relevance, performed the clinical trials, and analyzing the potential efficacy ofthe novel therapy (promoting metabolism) in hypersomnia patients.

Sleep Disorders46

Department of Psychiatry and Behavioral Sciences
Project
LeaderKazutaka Ikeda Addictive Substance Project

Addictive Drugs are Double-edged Swords:
They can become both harmful and beneficial
depending on how they used

Sugaya N, Ogai Y, Aikawa Y, Yumoto
Y, Takahama M, Tanaka M, Haraguchi A, Umeno M, and Ikeda K. (2018)“A randomized controlled study ofthe effect of ifenprodil on alcohol use
in patients with alcohol dependence.”
Neuropsychopharmacology Rep.
Yamamoto H, Kamegaya E, Hagino
Y, Takamatsu Y, Sawada W, Matsuzawa M, Ide S, Yamamoto T, Mishina M,
and Ikeda K (2017) Loss of GluN2D
subunit results in social recognition
deficit, social stress, 5-HT2C receptor
dysfunction, and anhedonia in mice.
Neuropharmacology 112, 88-197.
Ide S, Takahashi T, Takamatsu Y, Uhl
G, Niki H, Sora I, and Ikeda K (2017)“Distinct roles of opioid and dopamine
systems in lateral hypothalamic intracranial self-stimulation.“ Int. J. Neuropsychopharmacol. 20, 403-409.
Fujita M, Hagino Y, Takeda T, Kasai
S, Tanaka M, Takamatsu Y, Kobayashi K, and Ikeda K (2017) “Light/
dark phase-dependent spontaneous
activity is maintained in dopamine-deficient mice.“ Mol. Brain.10, 49.
Nishizawa D, Fukuda K, Kasai S,
Hasegawa J, Aoki Y, Nishi A, Saita
N, Koukita Y, Nagashima M, Katoh R,
Satoh Y, Tagami M, Higuchi S, Ujike
H, Ozaki N, Inada T, Iwata N, Sora I,
Iyo M, Kondo N, Won MJ, Naruse N,
Uehara K, Itokawa M, Koga M, Arinami
T, Kaneko Y, Hayashida M, and Ikeda
K. (2014) “Genome-wide association
study identifies a potent locus associated with human opioid sensitivity.”
Mol. Psychiatry. 19, 55-62.
Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino O, Ikeda K, and Mizuguchi M. (2012) “Rapamycin reverses
impaired social interaction in mousemodels of tuberous sclerosis complex”
Nat. Communun. 3, 1292.

Addiction to substances (e.g. drugs, alcohol, tobacco) and behavior (e.g.
internet, gambling) is a serious public health problem. Moreover, use oflegal drugs has been increasing inJapan in recent years. It is importantto prevent and solve problems of addictions.
Addiction
On the other hand, some addictive
drugs are also widely used as analgesics and treatment of developmental
disorders. Thus, it is considered that
Developmental
Pain
disorderstreatment
some molecules involved in action of
addictive drugs are commonly related
to analgesics and developmental disorders.
The goals of our project are as follows: 1) Development of novel treatment and prevention of addiction. 2)
Improvement of personalized pain treatment. 3) Development of novel
treatment against developmental disorders.

“We are trying to improve treatment, prevention,and understanding of addiction, pain, anddevelopmental disorders by revealing the mechanisms
underlying addiction.”
All goals can make significant contribution to the society. We aim tothose goals through studying the action mechanisms of addictive drugs
using molecular biological approach, behavioral pharmacological approach, human genome analysis, and clinical approach.

Addictive Substance47

Department of Psychiatry and Behavioral Sciences

Members

Addictive Substance48

Department of Sensory and Motor Systems
Project
LeaderShinji Kakei Motor Disorders Project

From Neuron to Action and its Disorders

Tomatsu S, Ishikawa T, Tsunoda Y,
Lee J, Hoffman DS, Kakei S. Information processing in the hemisphere of
the cerebellar cortrex for motor controlof wrist movement. J Neurophysiol
115:255-270 (2016).
Ishikawa T, Tomatsu S, Izawa J, Kakei S. The cerebro-cerebellum:
Could it be loci of forward models?
Neurosci Res 104:72-79 (2016).
Lee J, Kagamihara Y, Kakei S. A new
method for functional evaluation of
motor commands in patients withcerebellar ataxia. PLoS One
10:e0132983 (2015)
Ishikawa T, Tomatsu S, Tsunoda Y, Lee
J, Hoffman DS, Kakei S. Releasing
dentate nucleus cells from Purkinje
cell inhibition generates outputs fromthe cerebrocerebellum. PLoS One
9:e108774 (pp.1-16) (2014).

We try to understand how the brain controls our movements in the realworld. We study the process of action generation at a single neuron level using animal models to understand how the movement is processedin the brain. We also study actions of healthy people, as well as thosewith neurological disorders, such as cerebellar disorders, Parkinson’s
disease or strokes. We look for building-blocks of motor control with multidisciplinary approaches. We employ both invasive and non-invasive
approaches to achieve the deepest understanding of our brain. Our tools
include various neurophysiological recording techniques (single unit recording, electromyography(EMG) and electro-encephalography (EEG)),brain stimulation, neuroimaging, analysis of movement kinematics and alarge-scale modeling. We have two long-term goals: 1) to understandthe basic function of the motor structures of the brain including the cerebellum, the basal ganglia, and the motor cortex; and 2) to understandhow our brain controls our movements on the basis of the findings in 1).

“Through our research, we are trying tounderstand the brain.
The brain was first created to control movement
and extended to control higher brain functions.”
CG by Katsunori Goto

“The brain mechanism
for motor control must
provide a basic framework
to understand higher
brain functions.”
The brain is an assembly of neural networks.
CG by Katsunori Goto

Motor Disorders49

Department of Sensory and Motor Systems

Motor Disorders50

Department of Sensory and Motor Systems
Project
LeaderTakayuki Harada Visual Research Project

Elucidation of Pathology and Developmentof Therapeutic Strategies for Retinal
Neurodegenerative Diseases

Kimura, A., Namekata, K., Guo, X.,
Noro, T., Harada, C., and Harada,T. (2015) “Valproic acid prevents
NMDA-induced retinal ganglion cell
death via stimulation of neuronal TrkB
receptor signaling.” Am. J. Pathol.
185, 756-764.
Noro, T., Namekata, K., Kimura, A.,
Guo, X., Azuchi, Y., Harada, C., Nakano, T., Tsuneoka, H., and Harada,T. (2015) “Spermidine promotes retinal
ganglion cell survival and optic nerve
regeneration in adult mice following
optic nerve injury.” Cell Death Dis. 6,e1720.
Harada, C., Guo, X., Namekata, K.,
Kimura, A., Nakamura, K., Tanaka, K.,
Parada, LF., and Harada, T. (2011)“Glia- and neuron-specific functions of
TrkB signalling during retinal degeneration and regeneration.”
Nature Commun. 2, 189.

More than 1.6 million people in Japan are visually impaired, representing
economic social losses estimated at more than 8 trillion yen. In the particular context of the increased penetration of Western lifestyles andan aging society, the increase in the number of patients with conditions
such as glaucoma and diabetic retinopathy, which could be called“adult eye diseases,” has become a major social issue.
To achieve improved quality of life (QOL) for the visually impaired in an
increasingly aging population, we seek to elucidate detailed
pathogenic mechanisms and develop new therapies through thedevelopment of a model of intractable eye disease.

“We are focusing on elucidating the molecularmechanisms of neuroprotection and neuroregeneration, and our final goal is the prevention or treatment of blindness in retinal neurodegenerative
disorders such as glaucoma and traumatic injury.”

Guo, X., Harada, C., Namekata, K.,
Matsuzawa, A., Camps, M., Ji, H.,
Swinnen, D., Jorand-Lebrun, C., Muzerelle, M., Vitte, P., Ruckle, T., Kimura,A., Kohyama, K., Matsumoto, Y., Ichijo,
H., and Harada, T. (2010) “Regulationof the severity of neuroinflammationand demyelination by TLR-ASK1-p38
pathway.” EMBO Mol. Med. 2, 504-515.
Harada, T., Harada, C., Nakamura, K.,
Quah, HA., Okumura, A., Namekata,K., Saeki, T., Aihara, M., Yoshida, H.,
Mitani, A., and Tanaka, K. (2007) “Thepotential role of glutamate transporters
in the pathogenesis of normal tension
glaucoma.” J. Clin. Invest. 117,
1763-1770.

Visual Research51

Department of Sensory and Motor Systems

Our major aim• To develop a neuroprotective retinal therapy using animal disease models• To elucidate the mechanisms involved in the onset of optic neuritis• To establish a method to promote regeneration of the optic nerve

Senior Research Scientist

Kazuhiko Namekata

Dock family proteins

Namekata,
K.,
Kimura,A.,
Kawamura, K., Harada, C., andHarada, T. (2014) “Dock GEFs andtheirtherapeuticpotential:
Neuroprotection
andaxon
regeneration.” Prog. Retin. Eye Res.
43, 1-16.

The dedicator of cytokinesis (Dock) family is composed of atypical guanine exchange factors (GEFs) that induce actin polymerization. To date,
11 Dock family members have been identified. Dock3 is predominantly
expressed in the central nervous system. In the growth cone, Dock3 induces actin polymerization by activating WASP family verprolin-homologous (WAVE) and modulates microtubule dynamics through inactivationof GSK-3β, leading to axon elongation. In addition, Dock3 plays a role inprotecting retinal ganglion cells from neurotoxicity and oxidative stress.
Dock3 may be a therapeutic target for optic neuropathy including glaucoma.

Namekata, K., Harada, C., Guo, X.,
Kimura, A., Kittaka, D., Watanabe,H., and Harada, T. (2012) “Dock3
stimulates axonal outgrowth via
microtubule
GSK-3β-mediatedassembly.” J. Neurosci. 32,264-274.
Namekata, K., Harada, C., Taya, C.,
Guo, X., Kimura, H., Parada, LF.,
and Harada, T.(2010) “Dock3
induces axonal outgrowth bystimulating membrane recruitment of
the WAVE complex.” Proc. Natl.
Acad. Sci. USA. 107, 7586-7591.

Axonal regeneration was enhanced
in Dock3 overexpressing mouse (Tg)
(Arrow heads indicate regenerating axons)

Visual Research52

Department of Sensory and Motor Systems
Project
LeaderYuki Nakayama ALS Nursing Care Project

Improving the Quality Of Life of Patientswith Amyotrophic Lateral Sclerosis

Nakayama Y, Shimizu T,Matsuda C,
Mochizuki Y, Hayashi K,Nagao M,
Kawata A, Isozaki E.(2017) “ Non-Motor Manifestations in ALS Patients with
Tracheostomy and invasive ventilation.” Muscle & Nerve.
Shimizu T, Takata K, Sakata A, Nagaoka.U, Ichihara N,Ishida C, Nakayama Y, Komori T, Nishizawa M. (2016)“The measurement and estimation of
total energy expenditure in Japanesepatients with ALS: A doubly labelledwater method study.” Amyotroph Lateral
Scler
Frontotemporal
Degener. 18, 37-45.
Mochizuki Y, Hayashi K, Nakayama
Y, Shimizu T, Kamide M, Ogino M,
Komori T, Hasegawa M, Isozaki E,
Nakano I. (2016) “IALS patients withability to communicate after long-term
mechanical ventilation have confined
degeneration to the motor neuron system.” J Neucol Sci. 363, 245-248.

“Our mission is to establish the best practices
for respiratory and communication management
for ALS patients in a community-based setting .
We have established a multidisciplinary researchteam to develop a Brain Machine Interface
for ALS patients.”

Matsuda C, Shimizu T, Nakayama
Y, Haraguchi M, Hakuta C, Itagaki Y,
Ogura A, Murata K, Taira M, Numayama T, Kinoshita M. (2016) “Macroglossia in advanced amyotrophic lateralsclerosis.” Muscle & Nerve. 54,
386-390.
Nakayama Y, Shimizu T, Mochizuki Y,
Hayashi K, Matsuda C, Nagao M, Watabe K, Kawata A, Oyanagi K, Isozaki
E, Nakano I. (2016) “Predictors of impaired communication in amyotrophic
lateral sclerosis patients with tracheostomy invasive ventilation.” Amyotroph
Lateral Scler Frontotemporal Degener. 17, 38-46.

ALS Nursing Care53

Department of Sensory and Motor Systems

ALS Nursing Care54

Department of Sensory and Motor Systems
Project
LeaderKazunori Sango Diabetic Neuropathy Project

Pathogenesis-based Therapeutic
Approaches to Diabetic Neuropathy

Sango, K., Mizukami, H,. Horie, H., andYagihashi, S. (2017) "Impaired axonal
regeneration in diabetes. Perspectiveon the under-lying mechanism from invivo and in vitro experimental studies."
Front. Endocrinol. 8, 12.

Peripheral neuropathy is one of the most common complications of Diabetes Mellitus, and its irritating symptoms such as pain and numbness
can be the cause of insomnia and depression, and when allowed toprogress to more advanced disease stages can result in serious consequences such as lower limb amputation and lethal arrhythmia. In addition, recent studies have indicated that diabetes is a major risk factor forcognitive disorders such as Alzheimer’s disease.

“We are trying to improve QOL
for diabetics and help them tolive longer lives by elucidating
the pathogenesis of neurologicaldisorders and establishingeffective treatments.”

Niimi, N., Yako, H., Tsukamoto, M.,
Takaku, S., Yamauchi, J., Kawakami,E., Yanagisawa, H., Watabe, K., Utsunomiya, K., and Sango, K. (2016)
Involvement of oxidative stress andimpaired lysosomal degradation in
amiodarone-induced schwannopathy.
Eur. J. Neurosci. 44, 1723-1733.
Suzuki, M., Fujikake, N., Takeuchi, T.,
Kohyama-Koganeya, A., Nakajima, K.,
Hirabayashi, Y., Wada, K., and Nagai,
Y. (2015) Glucocerebrosidase deficiency accelerates the accumulationof proteinase K-resistant α-synuclein
and aggravates neurodegeneration ina Drosophila model of Parkinson’s disease. Human Mol. Genet. 24, 66756686.
Tsukamoto, M., Niimi. N., Sango, K.,
Takaku, S., Kanazawa, Y., and Utsunomiya, K. (2015) Neurotrophic andneuroprotective properties of exendin-4 in adult rat dor-sal root ganglion
neurons: involvement of insulin and PI3
kinase/RhoA signaling. Histochem.
Cell Biol. 144, 249-259.

The goals of our project are as follows: 1) Establishing effective pathogenesis-based treatments for diabetic peripheral neuropathy. 2) Elucidating mechanistic link between metabolic dysfunction and neurodegenerative diseases.

Tomoyo Akamine
Masaki Oba

Naoko Niimi

Shizuka Takaku

Sango, K., and Yamauchi, J. (2014)
Schwann Cell Development and Pathology. Springer Japan K.K.
Takaku, S., Yanagisawa, H., Watabe,K., Horie, H., Kadoya, T., Sakumi. K.,
Nakabeppu, Y., Poirier, F., and Sango, K. (2013) GDNF promotes neurite outgrowth and up-regulates galectin-1 through the RET/PI3K signaling in
cultured adult rat dorsal root ganglion
neurons. Neurochem. Int. 62, 330-339.

Mari Suzuki

Diabetic Neuropathy
55

Hideji Yako

Department of Sensory and Motor Systems

Wild-type

MutantDiabetic Neuropathy
56

Department of Advanced Science for Biomolecules
Project
LeaderHiroyuki Sorimachi* Calpain Project* passed away on Jan. 6, 2018 and taken over by Yasuko Ono

Calpain: Structure-Function Relationships
Exploring calpain-mediated biological modulation

Hata, S., Kitamura, F., Yamaguchi, M.,
Shitara, H., Murakami, M., Sorimachi,
H. (2016) “A Gastrointestinal Calpain
Complex, G-calpain, Is a Heterodimerof CAPN8 and CAPN9 Calpain Isoforms, Which Play Catalytic and Regulatory Roles, Respectively.” J. Biol.
Chem., 291, 27313-27322.
Ono, Y., Saido, T.C., Sorimachi, H.
(2016) “Calpain research for drug
discovery: challenges and potential.”
Nature Reviews: Drug Discovery,
15, 854-876.
Shinkai-Ouchi, F., Koyama, S., Ono, Y.,
Hata, S., Ojima, K., Shindo, M., duVerle, D., Ueno, M., Kitamura, F., Doi, N.,
Takigawa, I., Mamitsuka, H., Sorimachi, H. (2016) “Predictions of cleavability of calpain proteolysis by quantitative
structure-activity relationship analysis
using newly determined cleavage sites
and catalytic efficiencies of an oligopeptide array.” Mol. Cell. Proteomics,
15, 1262-1280.
Ojima, K., Ono, Y., Hata, S., Noguchi,
S., Nishino, I., Sorimachi, H. (2014)“Muscle-specific calpain-3 is phosphorylated in its unique insertion region
for enrichment in a myofibril fraction.”
Genes Cells, 19, 830-841.
Tonami, K., Hata, S., Ojima, K., Ono,
Y., Kurihara, Y., Amano, T., Sato, T.,
Kawamura, Y., Kurihara, H., Sorimachi,
H. (2013) “Calpain-6 deficiency promotes skeletal muscle development
and regeneration.” PLoS Genet., 9,e1003668.
Hata, S., Abe, M., Suzuki, H., Kitamura,F., Toyama-Sorimachi, N., Abe, K.,
Sakimura, K., Sorimachi, H. (2010)“Calpain 8/nCL-2 and calpain 9/nCL-4
constitute an active protease complex,
G-calpain, involved in gastric mucosal
defense.” PLoS Genet., 6, e1001040.
Ojima, K., Kawabata, Y., Nakao, H.,
Nakao, K., Doi, N., Kitamura, F., Ono,
Y., Hata, S., Suzuki, H., Kawahara,
H., Bogomolovas, J., Witt, C., Ottenheijm, C., Labeit, S., Granzier, H.,
Toyama-Sorimachi, N., Sorimachi, M.,
Suzuki, K., Maeda, T., Abe, K., Aiba,
A., Sorimachi, H. (2010) “Dynamic distribution of muscle-specific calpain inmice has a key role in physical-stressadaptation and is impaired in muscular
dystrophy.” J. Clin. Invest., 120, 26722683.

Calpain57

Proteins are chains of amino acids, and their functions change by partial cuts.
Calpains are enzymes that
perform such “cuts” or “limited proteolytic processing”
in cooperation with calcium.
Humans have 15 calpain
species. Defects of either
calpain cause various deficiencies, such as muscular
dystrophy, stomach ulcer,“Translational research involving calpains is stillat the developmental stage. We need to learn more
about the calpains themselves, as well as their impact on various physiological systems and molecular pathways.” (Nat. Rev. Drug Discov. 2016)
and embryonic lethality. Calpains from infectious organisms also playessential roles in their pathogenicity; thus, calpains are promising targets in combat with infectious diseases like malaria, schistosomiasis,and periodontitis. Furthermore, calpains provide attractive subjects inprotein science; was an original calpain structure anciently generated
by fusion of protease and calciumbinding domains?
In this project, we aim to understand biology of calpains with wide
scope of interest, and translate the knowledge to the development of
our health as well as science.

Department of Advanced Science for Biomolecules

Senior Research Scientist

Yasuko Ono

Calpains in health and disease:

Exploring calpain-mediated biological modulation

Ono, Y., Ojima, K., Shinkai-Ouchi, F.,
Hata, S., Sorimachi, H. (2016) “An
eccentric calpain, CAPN3/p94/calpain-3.” Biochimie, 122, 169-187.
Ono, Y., Shindo, M., Doi, N., Kitamura, F., Gregorio, C.C., Sorimachi, H.
(2014) “The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3
restore proteolytic activity by intermolecular complementation.” Proc. Natl.
Acad. Sci. USA, 111, E5527-5536.
Ono, Y., Iemura, S., Novak, S.M., Doi,N., Kitamura, F., Natsume, T., Gregorio, C.C., Sorimachi, H. (2013)“PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1.” J.
Mol. Biol., 425, 2955-2972.

Some calpains predominantly expressed in specific tissue(s) are responsible for genetic diseases; e.g., defects in CAPN3 cause muscular dystrophy. Other calpains with rather ubiquitous expression pattern lead tolethality if deficient.
To explore how calpains
are usually protecting
our health, analysesof mice lacking one of
calpain genes, using
biochemistry including
proteomics, genetics,
and bioinformatics, arebeing performed.

Ono, Y., Sorimachi, H. (2012) “Calpains: an elaborate proteolytic system.” Biochim. Biophys. Acta, 1824,
224-236.
Ono, Y., Ojima, K., Torii, F., Takaya,
E., Doi, N., Nakagawa, K., Hata, S.,
Abe, K., Sorimachi, H. (2010) “Skeletal muscle-specific calpain is an intracellular Na+-dependent protease.” J.
Biol. Chem., 285, 22986-22998.

Calpain58

Department of Advanced Science for Biomolecules
Project
LeaderNoriyuki Matsuda Ubiquitin Project

Ubiquitin-MediatedMitochondrial Quality Control:
A shield against parkinson’s disease

Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C., Sou, Y-S.,
Saiki, S., Kawajiri, S., Sato, F., Kimura,M., Komatsu, M., Hattori, N. andTanaka, K. (2010) PINK1 stabilized by
mitochondrial depolarization recruits
Parkin to damaged mitochondria andactivates latent Parkin for mitophagy.
J. Cell Biology, 189, 211-221.
Okatsu, K., Oka, T., Iguchi, M., Imamura, K., Kosako, H., Tani, N., Kimura,M., Go, E., Koyano, F., Funayama,
M., Shiba-Fukushima, K., Sato, S.,
Shimizu, H., Fukunaga, Y., Taniguchi,
H., Komatsu, M., Hattori, N., Mihara,K., Tanaka, K., and Matsuda, N. (2012)
PINK1 autophosphorylation upon
membrane potential dissipation isessential for Parkin recruitment to damaged mitochondria. Nature Commun.
3 : e1016 (10 pages).
Koyano, F., Okatsu, K., Kosako, H.,
Tamura, Y., Go, E., Kimura, M., Kimura,Y., Tsuchiya, H., Yoshihara, H., Hirokawa, T., Endo, T., Fon, E-A., Trempe, JF., Saeki, Y., Tanaka, K., and Matsuda,
N. (2014) Ubiquitin is phosphorylated
by PINK1 to activate Parkin. Nature,
510, 162-166.
Matsuda, N. and Tanaka, K. (2015)
Tagged tags engage disposal. Nature, 524, 294-295.
Okatsu, K., Koyano, F., Kimura, M.,
Kosako, H., Saeki, Y., Tanaka, K., andMatsuda, N. (2015) Phosphorylated
ubiquitin chain is the genuine Parkin
receptor. J. Cell Biology, 209,111-128.

Ubiquitin
59

Ubiquitin is well-known as a signal for proteasome-dependent degradation; however, it also functions in autophagic degradation. Increasing
evidence indicates that selective autophagy functions in intracellularquality control by using ubiquitin tags to delineate aggregated proteinsand damaged organelles for degradation.
In 2000, Dr. Mizuno and Dr. Hattori (Juntendo Univ.) collaboration
with Dr. Suzuki and Dr. Tanaka (TMiMS) reported for the first timethat Parkin, which is a causative gene product of familial Parkinson’s
disease (PD), is an ubiquitin-protein ligase (Nat Genet 2000). In
addition, the identification of another gene PINK1 that linked to thefamilial forms of hereditary recessive early-onset PD (Science 2004)
has revealed that phosphorylation, ubiquitylation, and mitochondrial
integrity are key factors in disease pathogenesis. Nevertheless, theexact mechanism underlying the functional interplay between Parkin
and PINK1 remained an enigma. We thus have investigated how PINK1and Parkin cooperate to keep mitochondrial integrity against
mitochondrial stresses.

“We found that low-quality mitochondria aremarked with ubiquitin for selective degradation,and the key factors in this process are PINK1(a mitochondrial kinase) and Parkin (a ubiquitin
ligase), two proteins implicated in Parkinson’s
disease.”PINK1 is a mitochondrial Ser/Thr kinase whereas Parkin is a ubiquitin-protein ligase that catalyzes ubiquitylation of diverse mitochondrial
outer membranous proteins (J Cell Biol 2010). We revealed that PINK1
is rapidly and constitutively degraded under steady-state conditions in a
mitochondrial membrane potential-dependent manner but that a loss inmitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation (J Cell Biol 2010). Previously our and other groups found that
PINK1 acts as an upstream factor for Parkin, but how PINK1 activates
latent Parkin and recruits cytoplasmic Parkin to damaged mitochondria
were still obscure.

Department of Advanced Science for Biomolecules

Ubiquitin60

Department of Advanced Science for Biomolecules
Project
LeaderTakahiko Hara Stem Cell Project

Blood regeneration from ESC/iPSC anddevelopment of novel anti-cancer drugs

K. Kitajima, K. Minehata, K. Sakimura,
T. Nakano, and T. Hara. (2011) In vitro
generation of HSC-like cells from murine ESCs/iPSCs by enforced expression of LIM-homeobox transcription
factor Lhx2. Blood, 117, 3748-3758.

Dr. Yamanaka’s inducible pluripotent stem cell (iPSC) technology has
opened a new avenue to overcome incurable diseases by transplantation of missing cells. In 2011, we discovered that overexpression of
Lhx2 in hemogenic mesodermal cells resulted in ex vivo expansion oftransplantable hematopoietic stem cells (HSCs) from mouse embryonicstem cells (ESCs) and iPSCs. Since then, we are making great efforts toimprove the system and apply this method to human iPSCs. We believethat comparison of the in vitro differentiation capacity of hematopoietic
cells between mouse and human iPSCs would uncover novel and fundamental aspects of human HSC development.

K. Tanaka, K. Kondo, K. Kitajima, M.
Muraoka, A. Nozawa, and T. Hara.
(2013) Tumor-suppressive function ofprotein-tyrosine phosphatase non-receptor type 23 in testicular germ celltumors is lost upon overexpression of
miR142-3p microRNA. J. Biol. Chem.,
288, 23990-23999.

“We are making efforts to derive HSCs from human
iPSCs in vitro. We are also challenging to develop
novel anti-leukemia drugs and chemokine-based
anti-cancer drugs.”

K. Kitajima, M. Kawaguchi, M. Iacovino, M. Kyba, and T. Hara. (2013) Molecular functions of the LIM-homeobox
transcription factor Lhx2 in hematopoietic progenitor cells derived frommouse embryonic stem cells. StemCells, 31, 2680-2689.
Y. Kodaka, K. Tanaka, K. Kitajima, K.
Tanegashima, R. Matsuda, and T.
Hara.(2015) LIM homeobox transcription factor Lhx2 inhibits skeletal muscle
differentiation in part via transcriptional
activation of Msx1 and Msx2. Exp. CellRes., 331, 309-319.
T. Suzuki, Y. Kazuki, M. Oshimura, andT. Hara. (2016) Highly efficient transfer of chromosomes to a broad rangeof target cells using Chinese hamster
ovary cells expressing murine leukemia virus-derived envelope proteins.
PLoS ONE, 11, e0157187.
K. Tanegashima, Y. Sato-Miyata, M.
Funakoshi, Y. Nishito, T. Aigaki, and T.
Hara. (2017) Epigenetic regulation of
the glucose transporter gene Slc2a1
by b-hydroxybutyrate underlies preferential glucose supply to the brain of
fasted mice. Genes Cells, 22, 71-83.

Stem Cell
61

The presence of cancer stem cells has been proposed in various typesof human cancer. As with tissue stem cells, cancer stem cells reside ina niche and stay dormant, thereby surviving chemotherapy and radiotherapy. Presumably, both tissue and cancer stem cells commonly express critical transcriptional regulators and signal transducers. We havealready identified DDX1 and PTPN23 as essential molecules for the onset of testicular tumors.
In 2007, we discovered that CXCL14, a CXC-type chemokine, is oneof the causative factors for obesity-associated diabetes. In contrast,
CXCL14 is known to possess tumor-suppressive activity against lungand oral carcinomas. Recently, we discovered that CXCL14 binds to
CXCR4 with high affinity, thereby inhibiting the CXCL12-mediated cell
migration. This could be one of the underlying mechanisms of the CXCL14’s anti-tumor function. We are vigorously investigating physiologicalroles of CXCL14 and its action mechanisms. CXCL14 is a promising toolfor developing novel anti-cancer and anti-diabetes drugs.

Department of Advanced Science for Biomolecules

Stem Cell
62

Department of Advanced Science for Biomolecules
Project
LeaderYuichiro Miyaoka Regenerative Medicine Project

Genome Editing in Human iPS Cells:
To study and cure genetic disorders

Miyaoka Y, Chan AH, Judge LM, Yoo
J, Huang M, Nguyen TD, Lizarraga PP,
So PL, Conklin BR. (2014) “Isolationof single-base genome-edited human
iPS cells without antibiotic selection.”Nat. Methods 11, 291-293.
Mandegar MA, Huebsch N, Frolov EB,
Shin E, Truong A, Olvera MP, Chan
AH, Miyaoka Y, Holmes K, Spencer
CI, Judge LM, Gordon DE, Eskildsen
TV, Villalta JE, Horlbeck MA, Gilbert
LA, Krogan NJ, Sheikh SP, Weissman
JS, Qi LS, So PL, Conklin BR. (2016)“CRISPR Interference Efficiently Induces Specific and Reversible Gene
Silencing in Human iPSCs.” Cell Stem
Cell 18, 541-553.
Miyaoka Y, Berman JR, Cooper
SB, Mayerl SJ, Chan AH, Zhang B,
Karlin-Neumann GA, Conklin BR.
(2016) “Systematic quantification of
HDR and NHEJ reveals effects oflocus, nuclease, and cell type on genome-editing.” Sci. Rep. 6, 23549.
Miyaoka Y, Chan AH, Conklin BR.
(2016) ”Using Digital Polymerase
Chain Reaction to Detect Single-Nucleotide Substitutions Induced by
Genome Editing.” Cold Spring Harb.
Protoc.
Nguyen DP, Miyaoka Y, Gilbert LA,
Mayerl SJ, Lee BH, Weissman JS,
Conklin BR, Wells JA. (2016) “Ligand-binding domains of nuclear receptors facilitate tight control of split
CRISPR activity.” Nat. Commun. 7,12009.
Workman MJ, Mahe MM, Trisno S,
Poling HM, Watson CL, Sundaram
N, Chang CF, Schiesser J, Aubert P,
Stanley EG, Elefanty AG, Miyaoka Y,
Mandegar MA, Conklin BR, Neunlist
M, Brugmann SA, Helmrath MA, Wells
JM. (2017) “Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous
system.” Nat. Med. 23, 49-59.

Genome editing technology allows us to rewrite the genetic informationin virtually any species and any cell type including human cells. To study
the pathogenesis of human diseases at the molecular level, and to develop new therapies using genome editing, we need appropriate humancellular models. Our focus is on human iPS (induced pluripotent stem)
cells, a type of pluripotent stem cell that can be generated from patients’cells by introduction of specific transcription factors, and differentiatedinto other cell types. Our goal is to use genome editing of iPS cells toboth model human diseases, and develop new therapies.

“Our goal is to develop methods to precisely and efficiently edit the genome in human iPS cells to allow
us to develop disease models using human cells, anddevelop new therapies for these diseases.”

We developed an efficient method to isolate iPS cell lines containing asingle nucleotide substitution. The nucleotide substitution is created bygenome editing based on digital PCR, and isolation is accomplished byrepeated limited dilutions in the absence of selection markers (Miyaoka,Nat. Methods 2014). Using this method, we are analyzing the pathogenesis of cardiomyopathy caused by point mutations of RBM20 (RNA-binding
motif protein 20) in isogenic cardiomyocytes derived from genome-edited
iPS cells. We are also improving the precision and efficiency of genome
editing technology, anddeveloping new therapies based on correcting
mutations in iPS cells
from patients. In addition, we are developinga strategy to directly edit
the genome in cells in
the human body.

Regenerative Medicine
63Department of Advanced Science for Biomolecules

Members

Regenerative Medicine
64Department of Advanced Science for Biomolecules
Project
LeaderTakashi Shichita Stroke Renaissance Project

Sterile Inflammation
After Ischemic Stroke

Shichita T, et al. (2017) Mafb prevents
excess inflammation after ischemic
stroke by accelerating clearance of
danger sig-nals through MSR1. Nat
Med. 23, 723-732.
ShichitaT,etal.
(2012)
Peroxiredoxin family proteins are key
initiatorsofpost-isch-emic
inflammation in the brain. Nat Med.
18, 911-917.
Shichita T, et al. (2009) Pivotal role of
cerebralinterleukin-17-producing
gammadelta T cells in the delayedphase of isch-emic brain injury. Nat
Med. 15, 946-950.

“What triggers neural
repair after stroke?”We have identified peroxiredoxin family proteins as DAMPs (damage
associated molecular patterns) which trigger the post-ischemic inflammation (Nat Med 2012). DAMPs induce IL-23 production from infiltrating
macrophages and neutrophils, and this sustains the inflammation after
ischemic stroke by promoting IL-17 production of gdT lymphocytes (NatMed 2009). Cerebral post-ischemic inflammation resolves several days after the stroke
onset. The clearance of DAMPs from ischemic brain through MSR1, a scavenger receptor, plays a pivotal role in the resolutionof sterile inflammation after ischemic stroke(Nat Med 2017). Now our question is how
the cerebral post-ischemic inflammation
switches into the process of neural repair.

Stroke Renaissance65

Department of Advanced Science for Biomolecules

Stroke Renaissance66

Department of Advanced Science for Biomolecules

Unit Leader

Kohji Kasahara Biomembrane Unit

Physiological Functions of Lipid Rafts /Glycosphingolipid Microdomains inTransmembrane Signaling

Kasahara, K., Kaneda, M., Miki, T., Iida, K., Sekino-Suzuki, N., Kawashima,I., Suzuki, H., Shimonaka, M., Arai, M.,
Ohno-Iwashita, Y., Kojima, S., Abe,
M., Kobayashi, T., Okazaki, T., Souri, M., Ichinose, A., Yamamoto, N.
(2013) “Clot retraction is mediated byfactor XIII-dependent fibrin-aIIbb3-myosin axis in platelet sphingomyelin-richmembrane rafts.” Blood 122, 33403348.
Sekino-Suzuki , N., Yuyama, K., Miki,
T., Kaneda, M., Suzuki, H., Yamamoto, N., Yamamoto, T., Oneyama, C.,
Okada,M., Kasahara, K. (2013) “Involvement of gangliosides in theprocess of Cbp/PAG phosphoryla-tion
by Lyn in developing cerebellar growthcones.” J.Neurochem. 124, 514-522.
Kasahara, K., Souri, M., Kaneda, M.,
Miki, T., Yamamoto, N., Ichinose, A(2010) “Impaired clot retraction infactor XIII A subunit-deficient mice.“
Blood 115, 1277-1279.
Yuyama, K., Sekino-Suzuki, N., Sanai,Y., Kasahara, K. (2007) “Translocationof activated heterotrimeric G protein Gαo to ganglioside-enriched
detergent-resistant membrane rafts indeveloping cerebellum." J.Biol.Chem.
282, 26392-26400.
Kasahara, K., Watanabe, K., Takeuchi,
K., Kaneko, H., Oohira, A.,Yamamoto,T., and Sanai, Y. (2000) “Involvementof gangliosides in GPI-anchored neuronal cell adhesion molecule TAG-1
signaling in lipid rafts.” J.Biol.Chem.
275, 34701-34709.
Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y. (1997) “Associationof src family tyrosine kinase Lyn withganglioside GD3 in rat brain. Possible
regulation of Lyn by glycosphingolipid in caveolae-like domains.” J.Biol.
Chem. 272, 29947-29953.

Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and proteins that can be stabilized into microdomains
involved in the regulation of a number of cellular processes.
We have been investigating the association of glycosphingolipids withspecific proteins in the nervous system and blood platelets.
We demonstrated that anti-ganglioside GD3 antibody co-precipitates
GPI-anchored neural cell adhesion molecule TAG-1, src-family kinase
Lyn, its substrate Cbp, trimeric G protein Goα of cerebellar granule cells.
TAG-1 plays roles in axonal
guidance, and cellular migration. GPI anchors have no
direct contact with the cytoplasm. We demonstrated that
TAG-1 transduces signal via
Ganglioside GD3-rich rafts
Lyn/Cbp in ganglioside GD3- of cerebellar granule cells
rich rafts of cerebellar granulecells. Chemokine SDF-1α triggers the chemoattraction of cerebellar
granule cells during cerebellar development.
We demonstrated that SDF-1α stimulates GTPγS binding to Goα, andcauses Goα translocation to lipid rafts, leading to growth cone collapseof cerebellar granule cells.

“We found that glycosphingolipids function
as platforms in transmembrane signaling
for the attachment of various signaling moleculesof neurons and platelets.”
Fibrin associates with lipid rafts on
the platelets and raft integrity is required for clot retraction. We proposethat clot retraction is mediated byfactor XIII-dependent fibrin-integrin
αIIbβ3-myosin axis in sphingomyelin-rich membrane rafts.

Sphingomyelin-rich rafts of platelets

Members: Ikuo Kawashima, Kiyoshi Ogura,
Tomohiro Iguchi, Keisuke Komatsuya

Biomembrane67

Center for Basic Technology Research
The Basic Technology Research Center provides multiple resources toassist the researchers of the institute conduct researches with the maximum efficiency. The services provided include state-of-the art technologies required for biomedical and life science researches at their highest
level, and maintenance of various facilities which are routinely used by
the researchers. Details of the services provided and specific activities ofrelated facilities are given below.

Head of Center

Minoru Saitoe

1. The Animal Research Division maintains the animal facility that isused by all the researchers who use animals for their research. It assists
researchers generate knock-out or transgenic animals as well as maintain
sperms and eggs of various lines of mutant animals. It also provides maximal care for the welfare of the animals used in the research.
2.
The Advanced Technical Support Department consists of Protein
Analyses, FACS, Microarray, Confocal Microscopy, Electron Microscopy,
and Histology Laboratories etc. and offers state-of-the-art technology to
the researchers.
3. The Information Support Department consists of Library, Information
Technology Section, Media Technology Laboratory and Public Relation Office. It assists researchers search for references, provides supports fordaily use of computer systems, and deals with the media.
4. The Authorized and General Core Facility Department consists of Radioisotope Laboratory, Hazardous Chemical Control Room and General
Common Facility, and provides the researchers with various special andcommon facility as well as safety regulations for accident-free daily operation of the institute.

68Technology Licencing Office (TLO)
Who we are
・ The Technology Licensing Office (TLO) facilitates the conversion ofscientific discoveries to innovative technologies with the ultimate goalof improving public health and welfare.
・ We evaluate basic research findings (seeds) as intellectual property
assets, and license promising candidates to industries for development
as medicines, diagnostics, medical devices, foods, cosmetics andresearch tools.
General Manager

Futoshi Shibasaki, MD, PhD

Senior Manager

Kazumasa Aoki, PhD

What we do・ We manage intellectual properties from our institute including
patents, copyrights and materials in order to develop them forcommercialization.
・ To promote technology transfer, we introduce seeds and intellectual properties with potential commercial value to pharmaceutical, medical device, and startup companies.
・ We attend business meetings such as the BIO international convention in the US and BioJapan, todevelop Public Private Partnership (PPP) opportunities between our institute and industries.
We support collaborative research projects with industries by arranging Joint Research Agreements,
・ Material Transfer Agreements (MTA), and other contracts to protect and develop a wide range of
research discoveries.

69

Center for Medical Research Cooperation
Making the Dream ofYoung Scientists Come True
– from bench to bed and back again –Head of Center

Masanari Itokawa

We provide---Consultation on statistical analyses-Ethical issues related to human specimens-A bridge between basic scientists and medical doctors

7,000 beds ofTokyo Metropolitan Hospitals

Tokyo Metropolitan Institute of Medical Science

We provide tools for developing medical technology from
simple findings at the bench; the process similar to making abrilliantly sparkling jewelry by cutting a piece of crude stone.
We provide consultation on statistical analyses of raw data.
We manage ethical issues related to human specimens. We
facilitate the communication between the basic scientists andmedical doctors.

Conference with researchers and medical doctors

Most of discovery of scientific research is unexpectedly made byscientists who still have very “flexible” scientific mind, the privilegeof young people.
A young scientist discussing with medical
doctors in a conference70Neuropathology Laboratory
Translational Research using humanmaterials and Management of
Database for Essential Brain Anatomy& Neuropathology
Laboratory Head

Nobutaka Arai

Neuropathology Database

Searchclick

Laboratory of Neuropathology (LONP) has more than 5,000 sets of human autopsied brain slides with awide variety of human neurological diseases. In recent years, we have been scanning these slides with
virtual slide instruments. Using those digital data and their derivatives, LONP is supposed to constructdigital neuropathology database which could contribute to society through e-learning of basic knowledge,
remote pathology and collaboration with neuroradiology. In addition, LONP has whole slide images of the
marmoset brain which is open to researchers.

Neuropathology
71Technical Researcher
Erika Seki

Brain Tissue Library
Stain Technology
Translational Research
Educational Lecture

Rika Kojima

Digital Pathology Archive
Stain Technology
Educational contents
e-Learning tool

Digital Pathology Coordinator

Nobuko Ueki Web coding, server management
Tomoko Yagi Whole slide image, Web design

Neuroscience Illustrator
Tsunemi YamanishiBrain image illustrating, E-learning image

If you have an interest in our e-Learning, “Essential Brain Anatomy & Neuropathology”,
Please e-mail to: pathology-db@igakuken.or.jp

To request your own user ID and password to access the full contents of the digital atlas,
Please e-mail to: ns-marmoset@igakuken.or.jp

72

TMiMS Programs
Seminars/ lectures and related activities
Scientific seminars:

We have scientific seminars by renowned scientists from Japan andoverseas almost every week in various subjects.

International Symposium:

We have three to four annual international symposium byinviting top-flight scientists from all over the world in various fields.

Science forum with industry:

We have annual forum hosted by our TLO office where scientists at
our institute introduce our discovery and discuss potential applications with scientists from industry.

In-house and delivery lectures to high school students:
We give lectures to visiting high-school students or visit high schools
to present lectures as a part of our effort to educate youngsters andintroduce them into the field of medical science.

Joint graduate school programme:

Many scientists at our institute have joint appointment as a lecture oras a visiting professor at various universities. Many undergraduate
and graduate students are conducting their master/ Ph.D. researches at our institute under the guidance of out scientists.

Open laboratory to graduate students:

Once a year we invite students to our institute, conduct presentationand give them opportunities to experience the laboratory.

Summer training courses:

We have annual summer training courses to provide in-house training on various experimental techniques.

Lectures to public:

We conduct public lectures (8 times a year) to let public know thescientific progress made at our institute and our various activities .

Science Café:

We have Café-style meetings (3-4 times a year) where we give
public the opportunities to learn, discuss and experience scienceand let them know the joy of science in a very casual setting.

Supports for young scientists
Research Associate Fellowship:

We provide graduate students who conduct their master/ Ph.D.
thesis research at our institute with research associate fellowship togive them financial support.

Travel support for young scientists attending aninternational meeting:

We provide students and young scientists of our institute with travel
fellowships with which they can attend international meetings
where they will present their latest findings.

73

Access Map
Tokyo Metropolitan Institute of Medical Science
Address

2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

Tel and Fax+81-3-5316-3100 & +81-3-5316-3150

http://www.igakuken.or.jp (Japanese) &http://www.igakuken.or.jp/english/ (English)

URL
Tohoku Shinkansen,
Joetsu Shinkansen,
Nagano Shinkansen

To Sendai, Nigata, Nagano
To Tsuchiura

Omiya

Narita Airport

Keisei Line

Ikebukuro

Narita Express

To Akabane,

Nippori
Ueno

Kichijoji

Shinjuku

Akihabara

Chuo Line, Sobu LineHach
Ka ima
m ny
ik am
ita
za a
w
a

To Tachikawa, Hachioji

Meidaimae

Keio

Line

Inokashira LineTokyo

Shibuya

AIRPORT to INSTITUTE

Chiba

From Narita Airport to Kamikitazawa Station / Hachimanyama Station
Narita Airport - Shinjuku Station

Yamanote Line

Shinjuku Station - Kamikitazawa or
Hachimanyama Station

Shinagawa

ji
achio
eio H
To K

JR Narita Express
Keio-Line

From Haneda Airport to Kamikitazawa Station / Hachimanyama Station

Keikyu Line

Haneda Airport

Tokyo Metropolitan Institute of Medical Science

Haneda Airport - Shinagawa Station

Keikyu Line

Shinagawa Station - Shinjuku Station

JR Yamanote Line

Shinjuku Station - Kamikitazawa or
Hachimanyama Station

Keio-Line

Tokaido Shinkansen,
Sanyou Shinkansen
To Nagoya, Osaka

Chofu

Shinjuku

KOSHU KAIDO

Keio Line

Hachimanyama

Kamikitazawa

Kamikitazawa Park

Hachimanyama St.

South exit

Matsuzawa Hospital

AT

AK
OR

ID

UM

UT

ORI

CHI D

A
KAMP

Shogun-ike ParkI
Hachimanyama

KOBAN

Matsuzawa
Park

Kamikitazawa 2-chome

From Kamikitazawa Station to Institute
Walk (approx. 10 min from the South exit of the station).
From Hachimanyama Station to InstituteBus (5 min from Hachimanyama stop to Kamikitazawa 2-chomestop [in front of the institute])74http://www.igakuken.or.jp/english/

As of February, 28, 2018