Institute for Genetic Medicine,
Hokkaido University

2022
2023

Contents● Aim and Mission

1● History

2● Chronological List of Director and Professor Emeritus

4● Organization

6● Staff

8● Research Activities
Research Section of Molecular Pathogenesis
Division of Stem Cell Biology

10Division of Signaling in Cancer and Immunology

12Division of Molecular Psychoimmunology

14

Division of Hepatitis Virology

18

Research Section of Pathophysiology
Division of Immunobiology

20

Division of Genome Biology

22

Division of Developmental Physiology

24

Division of Microbial Oncology

26

Research Section of Disease Control
Division of Functional Immunology

28

Division of Molecular Interaction

30

Division of Biomedical Oncology

32

Division of Biological Molecular Mechanisms

34

Frontier Research Unit
Molecular Cell Biology

36

Endowed Department
Department of Synbiotics

38

Attached Facility
Laboratory of Animal Experiments

40

R esearch Center for Infection-associated Cancer /Joint Usage ・ Research Center Promotion Office42● Education Activities

46● Campus Map of Hokkaido University

47

The Institute for Genetic Medicine (IGM) was established in
April 2000 by unifying the Institute of Immunological Science(formerly known as Hoppou Foundation for Tuberculosis Research), which was founded more than 60 years ago, and theCancer Institute affiliated with the School of Medicine, which
was founded over 40 years ago. Currently, IGM has 16 laboratories and facilities in total and performs research activities
mainly in the medical sciences in collaboration with other Departments at Hokkaido University including the School of
Medicine, Graduate School of Medicine, Department of Chemistry Graduate School of Science, Graduate School of Chemical Sciences and Engineering, Graduate School of Life Science,and Graduate School of Veterinary Medicine. In addition to its
faculty, IGM hosts more than 50 undergraduate and graduate
students as well as foreign students and visiting scientists fromvarious countries, giving it a total of about 200 members,
making it one of the largest research institutes for basic medical sciences and translational research in Eastern Japan. Since
2010, IGM has been certified by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) as a Joint Usage/Research Center for infection-associated cancers, such as
those caused by sustained infection with bacteria and viruses,
and therefore many researchers both inside and outside of

Institute for Genetic Medicine Aim and Mission

Director, Institute for Genetic Medicine,
Hokkaido University

Masaaki Murakami, Ph.D.

Japan visit IGM to perform relating research activities.
IGM has four core research areas: Infection, Cancer, Immunity and Inflammation. It aims to obtain new insights into thepathogenesis of diseases related to these areas and to develop novel treatment strategies by investigating from the molecular to in vivo levels how gene functions affect disease development. The institute encourages innovative andchallenging ideas from its researchers. This way of thinking is
intended to help discover new phenomena related to the disease pathogenesis and new prevention and therapeutic measures. In addition to research, IGM puts a strong emphasis on
the education of its young researchers. Therefore, we perform
various activities to support them. For example, we have started the Ichiro Azuma Foundation to provide oversea travel supports to our young investigators and been organizing the interdisciplinary symposium of Hokkaido University from 2015 togive them opportunities for collaborations in/out of Hokkaido
University. IGM has places an emphasis on community engagement, including coordinating events with local schools
and holding an annual IGM public exhibition.
With its emphasis on research and education and attention
to community service, IGM aims to make a strong impact onsociety by establishing new concepts in the life sciences andhelping translate these findings to clinical practice.
Nov. 2022

1

History
Institute of Immunological Science
1941. 2 Founded, Hoppou Foundation for Tuberculosis Research
1945. 8 Founded, Research Institute for Tuberculosis in Hoppou Foundation for Tuberculosis Reseach1950. 4 Founded, Research Institute for Tuberculosis, Hokkaido University. Established, Research Section ofProphylaxis and Research Section of Bacteriology
1951. 3 Donated, Building of Research Institute for Tuberculosis (1,935m2) from Hoppou Foundation for Tuberculosis Research
1951. 4 Established, Research Section of Chemistry and Research Section of Pathology in Research Institute for Tuberculosis
1953. 4 Established, Clinical Section in Research Institute for Tuberculosis
1954. 2 Started publishing periodically “Tuberculosis Research”
1968.11 Research Institute for Tuberculosis, Moved to North Building, Hokkaido University School of Medicine
1969. 4 Established, Research Section of Biochemistry in Research Institute for Tuberculosis, Hokkaido University
1974. 6 Research Institute for Tuberculosis, reorganized and Renamed, Institute of Immunological Science,
Hokkaido University. Established, Research Section of Bacterial Infection, Research Section of Serology, Research Section of Chemistry, Research Section of Pathology and Research Section of
Biochemistry in the Institute of Immunological Science
1975. 1 Started publishing periodically “Bulletin of the Institute of Immunological Science, Hokkaido University”
1976. 5 Established, Laboratory of Animal Experiment in Institute of Immunological Science
1980. 3 Started publishing periodically “Collected Papers from the Institute of Immunological Science,
Hokkaido University”
1980. 4 Established, Research Section of Cellular Immunology in Institute of Immunological Science, Hokkaido University
1990. 3 Discontinued, Research Section of Cellular Immunology in Institute of Immunological Science,
Hokkaido University
1990. 6 Established, Research Section of Immunopathogenesis in the Institute of Immunological Science,
Hokkaido University

Cancer Institute, School of Medicine
1962. 4 Founded, Cancer Immunopathology Institute, Hokkaido University School of Medicine, Established, Division of Pathology in the Cancer Immunopathology Institute1967. 4 Established, Division of Virology in Cancer Immunopathology Institute, Hokkaido University Schoolof Medicine
1969. 4 Cancer Immunopathology Institute, Hokkaido University School of Medicine was renamed Cancer Institute, Hokkaido University School of Medicine
1971. 4 Established, Division of Biochemistry in Cancer Institute, Hokkaido University School of Medicine
1979. 4 Established, Division of Genetics in Cancer Institute, Hokkaido University School of Medicine
1986. 3 Discontinued, Division of Genetics in Cancer Institute, Hokkaido University School of Medicine
1986. 4 Established, Division of Molecular Genetics in Cancer Institute, Hokkaido University School of Medicine
1992. 4 Established, Division of Cell Biology in Cancer Institute, Hokkaido University School of Medicine
1996. 3 Discontinued, Division of Molecular Genetics in Cancer Institute, Hokkaido University School of
Medicine
1996. 5 Established, Division of Gene Regulation and Division of Gene Therapy Development in Cancer
Institute, Hokkaido University School of Medicine
2Institute for Genetic Medicine
2000. 4
2004. 42006. 42008. 72010. 42011. 92012. 42013. 92013.102014. 2
2014. 32014. 42014. 52014.102015. 92017. 42017. 82017. 82018. 52018. 92020. 32020. 42020. 52020. 92020.102020.102021. 32021. 32021. 92022. 12022. 12022. 4

Founded, Institute for Genetic Medicine, Hokkaido University by integrating the Institute of Immunological Science, Hokkaido
University and the Cancer Institute, Hokkaido University School of Medicine
Established, Department of Matrix Medicine as Endowed Department in Institute for Genetic Medicine, Hokkaido University
Established, Division of ROYCE’ Health Bioscience as Endowed Department in Institute for Genetic Medicine, Hokkaido University
Laboratory of Animal Experiment for Disease Model was renamed Laboratory of Animal Experiments
Discontinued, Center for Virus Vector Development
Established, Center for Infection-associated Cancer
Authorized as a joint usage/research center for infection-associated cancers caused by sustained infection with bacteria
and viruses.
Established, Joint Usage/Research Center Promotion Office in Institute for Genetic Medicine, Hokkaido University
Established, Joint Office for Promoting Interdisciplinary Research in Institute for Genetic Medicine, Hokkaido University
Established, Department of Probiotics Immunology as Endowed Department in Institute for Genetic Medicine, Hokkaido University
Division of Cancer Related Genes was renamed Division of Stem Cell Biology
Division of Tumor Virology was renamed Division of RNA Biofunction
Discontinued, Department of ROYCE’ Health Bioscience as Endowed Department in Institute for Genetic Medicine, Hokkaido
University
Established, Biomedical Animal Research Laboratory as Frontier Research Unit in Institute for Genetic Medicine, Hokkaido
University
Discontinued, Department of Matrix Medicine as Endowed Department in Institute for Genetic Medicine, Hokkaido University
Established, Vascular Biology as Frontier Research Unit in Institute for Genetic Medicine, Hokkaido University
Division of Molecular Immunology was renamed Division of Molecular Neuroimmunology
Division of Immunoregulation was renamed Division of Functional Immunology
IGM was selected continuously as a joint usage/research center for infection-associated cancers caused by sustained infection with bacteria and viruses
Established, Liaison Labs in Research Center for Infection-associated Cancer
Division of Molecular Neuroimmnology was renamed Division of Molecular Psychoimmunology
Division of Molecular Virology was renamed Division of Developmental Immunology
Vascular Biology as Frontier Research Unit transferred to Faculty of Dental Medicine, Hokkaido University
Established, Division of Biomedical Oncology as Research Section of Disease Control in Institute for Genetic Medicine, Hokkaido University
Discontinued, Department of Probiotics Immunology as Endowed Department in Institute for Genetic Medicine, Hokkaido
University
Established, Department of Genome Biology as Division of Research Section of Pathophysioligy in Institute for Genetic Medicine, Hokkaido University
Established, Department of Synbiotics as Endowed Department in Institute for Genetic Medicine, Hokkaido University
Discontinued, Department of Molecular Oncology as Division of Research Section of Pathophysioligy in Institute for Genetic
Medicine, Hokkaido University
Established, Department of Developmental Physiology as Division of Research Section of Pathophysioligy in Institute for Genetic Medicine, Hokkaido University
Discontinued, Department of RNA Biofunction as Division of Research Section of Molecular Pathogenesis in Institute for Genetic Medicine, Hokkaido University
Established, Department of Molecular Cell Biology as Frontier Research Unit in Institute for Genetic Medicine, Hokkaido University
Discontinued, Joint Office for Promoting Interdisciplinary Research in Institute for Genetic Medicine, Hokkaido University
Discontinued, Department of Cancer Biology as Division of Research Section of Pathophysioligy in Institute for Genetic Medicine, Hokkaido University
Established, Department of Hepatitis Virology as Division of Research Section of Molecular Pathogenesis in Institute for Genetic Medicine, Hokkaido University
Established, Department of Biological Molecular Mechanisms as Division of Research Section of Disease Control in Institute for
Genetic Medicine, Hokkaido University
Established, Department of Microbial Oncology as Division of Research Section of Pathophysioligy in Institute for Genetic
Medicine, Hokkaido University
3Chronological List of Director and Professor Emeritus●S uccessive Director of Research Institute for Tu-

berculosis
Morio YASUDA, M.D.,Ph.D.

1950. 4-1953. 3

Yoshio TAKAHASHI, M.D.,Ph.D.

1953. 4-1968. 3

Shichiro KAKIMOTO, Ph.D.

1968. 4-1971. 3

Yoshio TAKAHASHI, M.D.,Ph.D.

1971. 4-1974. 3●S uccessive Director of Institute of Immunologi-

cal Science
Toru OHARA, M.D.,Ph.D.

1974. 4-1979. 4

Kazuo MORIKAWA, M.D.,Ph.D.

1979. 4-1985. 3

Ken-ichi YAMAMOTO, M.D.,Ph.D.

1985. 4-1988. 3

Ichiro AZUMA, Ph.D.

1988. 4-1994. 3

Mitsuaki KAKINUMA, M.D.,Ph.D.

1994. 4-1996. 3

Kazunori ONOÉ, M.D.,Ph.D.

1996. 4-2000. 3●S uccessive Director of Cancer Immunopatholo-gy Institute, School of Medicine
Katsuo TAKEDA, M.D.,Ph.D.

1962. 4-1965. 3

Sanshi ABE, M.D.,Ph.D.

1965. 4-1967.12

Hiroshi KOBAYASHI, M.D.,Ph.D.

1967.12-1969. 3●S uccessive Director of Cancer Institute, Schoolof Medicine

4

Hiroshi KOBAYASHI, M.D.,Ph.D.

1969. 4-1973. 3

Toyoro OSATO, M.D.,Ph.D.

1973. 4-1975. 3

Akira MAKITA, M.D.,Ph.D.

1975. 4-1977. 3

Hiroshi KOBAYASHI, M.D.,Ph.D.

1977. 4-1981. 3

Toyoro OSATO, M.D.,Ph.D.

1981. 4-1985. 3

Akira MAKITA, M.D.,Ph.D.

1985. 4-1989. 3

Toyoro OSATO, M.D.,Ph.D.

1989. 4-1993. 3

Noboru KUZUMAKI, M.D.,Ph.D.

1993. 4-1997. 3

Masaki SAITO, M.D.,Ph.D.

1997. 4-1997.10

Masuo HOSOKAWA, M.D.,Ph.D.

1997.11-2000. 3

●S uccessive Director of Institute for Genetic●S uccessive Director of Center for Infection-as-

Medicinesociated cancer, Institute for Genetic Medicine

Kazunori ONOÉ, M.D.,Ph.D.

2000. 4-2002. 3

Masanori HATAKEYAMA, M.D.,Ph.D.

2008. 7-2009. 6

Kenzo TAKADA, M.D.,Ph.D.

2002. 4-2006. 3

Akinori TAKAOKA, M.D.,Ph.D.

2009. 7-2012. 3

Toshimitsu UEDE, M.D.,Ph.D.

2006. 4-2010. 3

Kazuma TANAKA, Ph.D.

2012. 4-2014. 3

Kazuma TANAKA, Ph.D.

2010. 4-2012. 3

Toru KONDO, Ph.D.

2014. 4-2019. 3

Akinori TAKAOKA, M.D.,Ph.D.

2012. 4-2016. 3

Tetsuro HIROSE, Ph.D.

2019. 4-2020. 3

Masaaki MURAKAMI, V.M.D.,Ph.D.

2016. 4-2020. 3

Masaaki MURAKAMI, V.M.D., Ph.D.

2020. 4-2022. 3

Kazuma TANAKA, Ph.D.

2020. 4-2022. 3

Masahiro SONOSHITA, Ph.D.

2022. 4-Masaaki MURAKAMI, V.M.D.,Ph.D.

2022. 4●P
 rofessor Emeritus●S uccessive Director of Laboratory of Animal Ex-

Kazuo MORIKAWA, M.D.,Ph.D.

1985. 4

periment, Institute of Immunological Science

Ken-ichi YAMAMOTO, M.D.,Ph.D.

1988. 4

Kazuo MORIKAWA, M.D.,Ph.D.

1976. 5-1979. 3

Hiroyuki SHIOKAWA, Ph.D.

1988. 4

Jun ARIMA, M.D.,Ph.D.

1979. 4-1981. 3

Harue OKUYAMA, M.D.,Ph.D.

1991. 3

Ken-ichi YAMAMOTO, M.D.,Ph.D.

1981. 4-1985. 3

Hiroshi KOBAYASHI, M.D.,Ph.D.

1991. 4Ichiro AZUMA, Ph.D.

1985. 4-1988. 3

Akira MAKITA, M.D.,Ph.D.

1994. 4

Harue OKUYAMA, M.D.,Ph.D.

1988. 4-1991. 2

Mitsuaki KAKINUMA, M.D.,Ph.D.

1998. 4

Kazunori ONOÉ, M.D.,Ph.D.

1991. 2-1996. 3

Ichiro AZUMA, Ph.D.

1999. 4

Kazuyoshi IKUTA, M.D.,Ph.D.

1996. 4-1998.10

Masuo HOSOKAWA, M.D.,Ph.D.

2002. 4

Toshimitsu UEDE, M.D.,Ph.D.

1998.11-2000. 3

Kunimi KIKUCHI, M.D.,Ph.D.

2006. 4

Noboru KUZUMAKI, M.D.,Ph.D.

2006. 4

Kazunori ONOÉ, M.D.,Ph.D.

2009. 4

Kenzo TAKADA, M.D.,Ph.D.

2011. 4●S
 uccessive Director of Laboratory of Animal Ex-

periments, Institute for Genetic Medicine
Toshimitsu UEDE, M.D.,Ph.D.

2000. 4-2004. 3

Tetsuya MORIUCHI, M.D.,Ph.D.

2011. 4

Kunimi KIKUCHI, M.D.,Ph.D.

2004. 4-2006. 3

Toshimitsu UEDE, M.D.,Ph.D.

2013. 4Masanori HATAKEYAMA, M.D.,Ph.D.

2006. 4-2008. 6

Hisatoshi SHIDA, Ph.D.

2013. 4

Hisatoshi SHIDA, Ph.D.

2008. 7-2012. 3

Masayuki NOGUCHI, Ph.D.

2019. 4Masami MORIMATSU, D.V.M.,Ph.D.

2012. 4-2013.10

Ken-ichiro SEINO, M.D.,Ph.D.

2013.11-2017.10

Akinori TAKAOKA, M.D.,Ph.D.

2017.11-2021. 3

Ken-ichiro SEINO, M.D.,Ph.D.

2022. 4-●S
 uccessive Director of Center for Virus Vector

Development, Institute for Genetic Medicine
Kenzo TAKADA, M.D.,Ph.D.

2000. 4-2002. 3

Noboru KUZUMAKI, M.D.,Ph.D.

2002. 4-2006. 3

Hisatoshi SHIDA, Ph.D.

2006. 4-2008. 6

5

Organization

Division of Stem Cell Biology
Division of Signaling in Cancer and Immunology
Research Section of
Molecular Pathogenesis

Division of Molecular Psychoimmunology
Division of Hepatitis Virology
Division of Immunobiology
Division of Genome Biology

Research Section

Research Section of
Pathophysiology

Division of Developmental Physiology
Division of Microbial Oncology
Division of Functional Immunology
Division of Molecular Interaction

Research Section of
Disease Control

Division of Biomedical Oncology
Division of Biological Molecular Mechanisms

Frontier Research Unit

Molecular Cell Biology

Director
Professors’
MeetingLaboratory of Animal Experiments
Attached Facility
Research Center for Infection-associated Cancer

Endowed Department

Department of Synbiotics

Common Research Facility

Central Instrumentation Laboratory

Joint Usage ∙ Research Center Promotion Office

Technology Section

Administration Office6

Number of Staff

2022.6.1

Professor

13

Associate Professor

9

Lecturer

6

Assistant Professor

11

Administrative Officer

57

Technical Specialist・Technical Staff

5

Postdoctoral fellow

8

Research Fellow

3

Guest Researcher

12Part-time Fellow

3

Research Support Assistant5

Part-timer

13

Visiting Fellow

18

Total

Number of Student

163

2022.6.1

Graduate School of Medicine, Doctor Course

19

Graduate School of Medicine, Master Course

14

Graduate School of Chemical Sciences and0Engineering, Doctor Course
Graduate School of Chemical Sciences and5

Engineering, Master Course
Graduate School of Life Science, Doctor0

CourseGraduate School of Life Science, Master2

CourseSpecial Research Student

1

Visiting Student

47

Total

88

7

Staff

2022.6.1

Research Section of Molecular Pathogenesis

Research Section of Pathophysiology● Division of Stem Cell Biology● Division of Immunobiology
Ken-ichiro SEINO, M.D., Ph.D.

Professor

Toru KONDO, Ph.D.

Professor

Lecturer

You Lee SON, Ph.D.

Associate Professor

Haruka WADA, Ph.D.

Naoto OIKAWA, Ph.D.

Assistant Professor

Nanumi HAN, Ph.D.

Assistant Professor

Rei OKABE

Research Support Assistant● Division of Signaling in Cancer and Immunology
Professor

Akinori TAKAOKA, M.D., Ph.D.

Instructor

Seiichi SATO, Ph.D.

Assistant professor

Taisho YAMADA, Ph.D.

Technical Specialist

Nozomi SAKURAI

Part-time Fellow
Administrative AssistantAkihiro MORI

Part-time Fellow● Division of Genome Biology
Professor

Ken-ichi NOMA, Ph.D.

Associate Professor

Shinya OTA, Ph.D.

Hu HAKU

Technical Support Staff

Makiko FUKUUCHI

Chinami KATO

Administrative AssistantMichiko KANBAYASHI● Division of Developmental Physiology● Division of Molecular Psychoimmunology
Masaaki MURAKAMI, V.M.D., Ph.D.

Professor

Fumio MOTEGI, Ph.D.

Associate Professor

Shintaro HOJYO, Ph.D.

Lecturer

Kenji KIMURA, Ph.D.

Associate Professor

Shigeru HASHIMOTO, Ph.D.

Professor

Assistant Professor

Specially Appointed Lecturer Shimpei KUBOTA, M.D., Ph.D.
Specially Appointed Lecturer

Yuta SHINOHARA, Ph.D.

Specially Appointed Lecturer

Jing Jing JIANG, M.D., Ph.D.

Postdoctoral Researcher

Rieko NISHI, M.D., Ph.D.

Postdoctoral Researcher

Noriyuki HIRATA, Ph.D.

Research Fellow

Ikuko TAKAHASHITechnical Specialist

Chiemi NAKAYAMATechnical Assistant Staff

Naohumi SAKURAI

Technical Support Staff

Momoko TARU

Technical Support Staff

Eriko SASAKI

Technical Support Staff

Shiho TAKANO

Part-time Fellow
Administrative Assistant

Ami MATSUNOTechnical Staff● Division of Microbial Oncology
Associate Professor

Naoko KAMIYA, Ph.D.

Research Section of Disease Control● Division of Functional Immunology
Professor
Associate Professor

Toru KONDO, Ph.D.
Hidemitsu KITAMURA, Ph.D.

● Division of Molecular Interaction

Kumiko TANAKA, Ph.D.

Professor

Noriyo YAMAMOTO

Assistant Professor
Research Support Assistant● Division of Hepatitis Virology
Professor

Yukako NISHIMURA, Ph.D.

Administrative Assistant

Kohji MORIISHI, D.V.M., Ph.D.

8

Kazuma TANAKA, Ph.D.
Takuma KISHIMOTO, Ph.D.
Eriko ITO
Tomoko KURIBAYASHI● Division of Biomedical Oncology
Professor

Attached Facility

Masahiro SONOSHITA, Ph.D.

Assistant Professor

Takako OOSHIO, Ph.D.

Assistant Professor

Ryodai YAMAMURA

Technical Support Staff

Haruna OKUMURA

Technical Support Staff

Risa MIZUOCHI● Laboratory of Animal Experiments
Associate Professor● Division of Biological Molecular Mechanisms
Associate Professor

Yuko FUJIOKA, Ph.D.

Specially Appointed Assistant Professor

Daisuke NOSHIRO, Ph.D.

Specially Appointed Assistant Professor

Yuta OGASAWARA, Ph.D.

Technical Support Staff

Misa KAWAGOE

Technical Support Staff

Sachiko WATANABE

Technical Support Staff

Noriko MIMA
Hiroyuki MUROTA● Research Center for Infection-associated Cancer

Keina YODA

Administrative Assistant

Koki OTAKI

Technical expert

Nobuo N. NODA, Ph.D.

Professor

Kumiko YOSHIMATSU, DVM-Ph.D.

Technical Staff

Rie OGAWA

Research Support AssistantKen-ichiro SEINO, M.D., Ph.D.

Professor

Frontier Research Unit
● Molecular Cell Biology

Professor

Masahiro SONOSHITA, Ph.D.

Specially Appointed Professor

Masanori HATAKEYAMA, Ph.D.

Professor

Masaaki MURAKAMI, VMD-Ph.D.

Professor

Kohji MORIISHI, VMD-Ph.D.

Associate Professor

Hidemitsu KITAMURA, Ph.D.

Associate Professor

Naoko KAMIYA, Ph.D.

Associate Professor

Tomohiko OKAZAKI, Ph.D.

Associate Professor

Kumiko YOSHIMATSU, Ph.D.

Assistant Professor

Nao MORIMOTO, Ph.D.

Technical Specialist

Susumu ISHIKAWA

Technical Support Staff

Ayaka ABE

Technical Specialist

Satoko ISHIGAKI

Technical Support Staff

Noriko KATO

Research Support Assistant

Tomoko KURACHITechnical Support Staff

Humi YAMAMOTO● Joint Usage / Research Center Promotion Office

Endowed Department● Department of Synbiotics
Specially Appointed Professor

Tadaaki MIYAZAKI, Ph.D.

Specially Appointed Professor

Koichi SATO, Ph.D.

Specially Appointed Assistant Professor
Research Fellow

Kazunobu BABA, SC-Ph.D.
Yuki MIYAZAKI

Administrative AssistantNatsuki ZIN

Administrative AssistantRiho IIDUKA

9

Professor

Masahiro SONOSHITA, Ph.D.

Professor

Masaaki MURAKAMI, VMD-Ph.D.

Associate Professor

Hidemitsu KITAMURA, Ph.D.

Associate Professor

Kumiko YOSHIMATSU, Ph.D.

Technical Specialist

Susumu ISHIKAWA

Technical Specialist

Satoko ISHIGAKI

Research Support Assistant

Tomoko KURACHIResearch Section of Molecular Pathogenesis

Division of Stem Cell Biology

Professor Toru KONDO, Ph.D.
Research Project

Characterization of novel genes involved in agerelated CNS disorders, including glioma, and the developmentof new therapeutic methods for these diseases.
Outlinetion process; differences in cells of origin, such as stem
cells, precursor cells or differentiated cells; and the cancer

Our research objectives are to characterize the glioma-

microenvironment, in which GICs communicate with neu-

initiating cells (GIC), find GIC-specific factors, characterize

ral cells, endothelial cells and immune cells. Furthermore,

the factors and develop new therapeutic strategies forconsidering that various types of GICs can be generated

glioma. We also characterize factors that are involved in

at different time points of the transformation process,

NSC/OPC senescence and investigate their functions in

GBM very likely consists of heterogeneous GICs and their

the age-related disorders.

progeny. Because cancer cell heterogeneity is responsible
for therapy resistance, it is crucial to develop methods ofContents and Result

reducing such heterogeneity. Here, I summarize how GIC

Selective eradication of pluripotent stem cells by
inhibiting DHODH activity

and present how cell heterogeneity in cancer can be ad-heterogeneity is generated in the transformation processdressed based on recent findings.

For the success of regenerative medicine, it is crucial toNovel therapeutic approaches for metabolic
disorder via regulation of adipocyte function

establish methods that exclude the contamination of pluripotent stem cells (PSCs) in the differentiated cell population. The results of this study show that brequinar (BRQ),

There are two general classes of adipocytes; energy-

the strongest available inhibitor of dihydroorotate dehy-

storing white adipocytes and energy-expending browndrogenase (DHODH), specifically targets mouse PSCs (mP-adipocytes. Obesity and aging trigger adipose tissue re-SCs), whereas it is less cytotoxic toward lineage-commit-

modeling with changes in the number and size of the adi-

ted progenitor cells and differentiated functional cells.

pocytes, which ultimately lead to chronic low-grade in-Furthermore, BRQ prevents teratoma formation in vivo

flammation of the adipose tissue. Thus, obesity and aging

without any visible side effects in mice. These findings

are associated with the development of metabolic dis-

identify DHODH inhibitors, such as BRQ, as potential fun-eases such as type 2 diabetes and cardiovascular disease.

damental reagents for PSC-based cell therapy.

We have focused on the transmembrane receptor withunknown function in adipocyte which shows altered ex-

Glioblastoma-inhitiating cell heterogeneity generated by the cell-of-origin, genetic/epigenetic
mutation and microenvironmentpression depending on metabolic status. We found thatknockout mouse of this receptor is resistant to high fat
diet-induced obesity and related metabolic disorder such

Glioblastoma (GBM) and other malignant tumours con-as liver steatosis and insulin resistance, particularly viscer-

sist of heterogeneous cancer cells, including GBM-initiat-

al fat inflammation is reduced. Now we are trying to iden-

ing cells (GICs). This heterogeneity is likely to arise fromtify the molecular mechanism of the anti-obesity effect by

the following: different sets of genetic mutations and epi-

functional inhibition of this receptor.

genetic modifications, which GICs gain in the transforma-

http://www.igm.hokudai.ac.jp/stemcell/
10Figure 1. DHODH inhibitor BRQ selectively eliminates PSCs
Brequinar (BRQ), the available strongest inhibitor for the dihydroorotate dehydrogenase (DHODH), not only induces the activation of caspase 3 (Casp3) inpluripotent stem cells (PSCs) but also prevents tumorigenesis by eliminating PSCs expressing Oct4 and Nanog.

Figure 2. Tumour heterogeneity is generated by cell of origin, genetic mutation/epigenetic regulation and tumour environment factors(A) NSCs self-renew and generate neurons, astrocytes and oligodendrocytes. Similarly, glioblastoma-initiating cells (GICs) self-renew and generate
differentiation marker-positive cancer cells. It should be noted that OPCs acquire NSC characteristics and lose their specific characteristics in thetransformation process (reversion). (B) The first hit (red) occurs in the cell of origin of GIC. During proliferation, the mutant cells acquire further hits (yellow,
blue and grey), eventually generating GICs. Various combinations of hits in the p53, Rb and RTK signalling pathways can occur in proliferating mutant cells,
generating GIC heterogeneity. (C) Many types of tumour-surrounding cells, such as endothelial cells (EC), mesenchymal stem cells (MSCs), astrocytes,
microglia/macrophages and neurons, foster GICs by maintaining stemness/proliferation and supplying energy. In turn, GICs supply factors and increase
synapse formation to maintain their niche cells.

Teaching Staff

Lecturer

You Lee SON, Ph.D.

Assistant Professor

Selected Paper (2020.10-2022.5)

Naoto OIKAWA, Ph.D.

1. K ondo, T. (2021). Selective eradication of pluripotent stem cells by
inhibiting DHODH activity. Stem Cells, 39, 33-42.

Staff
Professor

・・・・・・・・・・・・・・・・・・ Toru KONDO, Ph.D.

Lecturer

・・・・・・・・・・・・・・・・・・ You Lee SON, Ph.D.

2. Kondo T. (2022). Glioblastoma-initiating cell heterogeneity generated by
the cell-of-origin, genetic/epigenetic mutation and microenvironment.
Semin Cancer Biol. 82, 176-183.
3. Son, Y.L., Ubuka, T., & Tsutsui, K. (2022). Regulation of stress responseon the hypothalamic-pituitary-gonadal axis via gonadotropin-inhibitory
hormone. Frontiers in Neuroendocrinology 64, 100953

Assistant Professor ・・・・・・・・・・・・・・・・・・ Naoto OIKAWA, Ph.D.

11

Research Section of Molecular Pathogenesis

Division of Signaling in Cancer and Immunology

Professor Akinori TAKAOKA, M.D., Ph.D.
Research Project(1) Elucidation of pathogen recognition mechanism(2) Novel regulatory mechanism of IFN-mediated antiviral innate defense(3) Implication of innate immune responses and cancer and inflammatory diseases
ferent from the host, and are specific to microorganisms such as nucleic acids and lip-

Outlineids. It was clarified that it is caused by recognizing the constituent molecules of. In virus

How does the host cell recognize the invasion of pathogenic microbes? Part ofinfection, virus-derived nucleic acids (RNA / DNA) often become PAMPs. In various viral

the sewer lies in the pattern recognition receptors in the innate immune system.

infections, nucleic acid recognition sensor molecules and their signal transduction

These receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible

pathways as shown in Fig. 1 have been clarified so far. In our laboratory, we are pro-gene-I (RIG-I), are innate sensors that mediate signal transductions inside the cells

ceeding with the identification of new nucleic acid recognition sensor molecules andto activate the induction of cytokines and chemokines (Figure 1). This leads to thethe analysis of the control mechanism of their signal transduction pathways.

activation of innate immune responses and the subsequent adaptive immune relecular patterns derived from host cells when the cells undergo necrosis/apopto-

Regulatory mechanism by aryl hydrocarbon receptor in type I IFN-mediated antiviral innate defense

sis, which may reflect aberrant inflammatory responses in autoimmune diseases.

Our research group has clarified the role of aryl hydrocarbon receptor (AHR) in vi-

sponses for the elimination of pathogens. Furthermore, PRRs can also sensor mo-

Research projects currently being conducted began in relation to the identifica-

rus-induced innate immune response (Yamada et al., Nat. Immunol., 2016). AHR is ation of DAI (DNA-dependent activator of IRFs), a DNA sensing molecule that acti-

ligand-activated transcription factor that mediates the toxicity of many environmental

vates innate immune responses. Recently, our laboratory identified ZAPS (Zincxenobiotics including dioxins, and also has important biophysiological roles. However,finger antiviral protein 1, shorter isoform) as a stimulator of RIG-I-mediated signaling during antiviral response. In addition, our research group has identified a cytosolic RNA sensor RIG-I as an innate sensor for hepatitis B virus (HBV) infection inhuman hepatocytes. There is also evidence indicating additional sensors of cytosolic DNA. The team is trying to explore such DNA and RNA sensor(s) and to elucidate underlying mechanisms of disease pathogenesis at a molecular level, in
terms of the function of the sensing molecules in the immune system. In particular,
the laboratory focuses on microbial infections, cancer, and autoimmune diseases.

Contents and Result
Elucidation of pathogen recognition mechanism
The immune system is an essential system for protecting the living body from the in-

Figure 1. Nucleic acid-mediated activation of innate immune signaling.

vasion of pathogenic microorganisms and maintaining the homeostasis of the living

Nucleic acid sensors are mainly divided into two groups; membrane-associated type andcytosolic type. Nucleic acid-ligand binding to sensors results in their association with theiradaptor proteins such as TRIF, MyD88, MAVS or STING, leading to the induction of IFNs
and inflammatory cytokines. On the other hand, some types of DNA also activate inflammasome, leading to the maturation of IL-1 β and IL-18. Abbreviations: TLRs, Toll-like receptors; RLRs, RIG-I-like receptors; NLRs, NOD-like receptors; ALRs, AIM2-like receptors; dsRNA, double-stranded RNA; ss-RNA, single-stranded RNA; rRNA, ribosomal RNA; Pol III, RNApolymerase III; 3pRNA, 5'-triphosphate RNA; cGAMP, cyclic GMP-AMP; IFNs, interferons.

body, and is roughly divided into innate immunity and acquired immunity. Of these, theinnate immune system, which first“recognizes”pathogenic microorganisms, is extremely important in that it initiates activation of the immune system. According tomany research results, in this pathogen recognition process, pattern recognition receptors (PRRs) are called pathogen-associated molecular patterns (PAMPs), which are dif-

http://www.igm.hokudai.ac.jp/sci/
12

its role in innate immune responses during viral infection is not fully understood. TypeI interferons (IFNs) are produced in response to viral infection and are crucial cytokines for the activation of antiviral immune responses. The induction of type I IFNs istriggered by the detection of the viral nucleic acids through pattern recognition receptors. In this study, we show that constitutive AHR signaling in the steady state
modulates type I IFN response during infection with various types of virus. The type I
IFN response was markedly enhanced in AHR-deficient mouse embryonic fibroblasts(MEFs) during infection with various types of virus. Such an excessive response wasalso observed upon pharmacological inhibition with an AHR antagonist or a TDO/IDO
inhibitor. Furthermore, we identified TIPARP as an AHR target gene that is essential for
AHR-mediated regulation of type I IFN production. Mechanistic studies revealed that

Figure 2.

TIPARP interacts and post-translationally ADP-ribosylates TBK1, resulting in the inhibi-

The schematic representation of constitutive AHR signaling for the TIPARP-mediatedmodulation of antiviral IFN response.

tion of its kinase activity. Thus, our findings demonstrate a novel link between AHRAHR signaling activated by endogenous ligands (Kyn, etc .) constitutively upregulates thelevels of TIPARP, which interacts with TBK1 for the downregulation of TBK1 activity by
ADP-ribosylation. This AHR-TIPARP axis plays a key role for tuning nucleic acid sensormediated type I IFN induction. TDO, tryptophan-2,3-dioxygenase; IDO, indoleamine-2,3dioxygenase; Kyn, kynurenine; TIPARP, TCDD-inducible poly(ADP-ribose) polymerase;
TBK1, TANK-binding kinase 1; IRF-3, interferon regulatory factor-3; IFN, interferon.

signaling and innate signaling for the modulation of IFN-mediated antiviral response
during viral infection, suggesting a physiological role of constitutive activation of the
AHR-TIPARP axis mediated by endogenous ligands such as tryptophan metabolites, in
restraining the IFN-dependent host antiviral defense system (Figure 2).

A novel mechanism of innate immune antiviral
response against SARS-CoV-2
COVID-19, caused by SARS-CoV-2, which is a positive-sense, single-stranded RNA
betacoronavirus, remains an ongoing global pandemic. Although most people infectedwith SARS-CoV-2 show a mild and self-limited course, there are also a few severe andcritical patients with exacerbated inflammatory response. The wide spectrum of clinical manifestations of COVID-19 suggests that individual immune responses to the underlying pathogen may play some crucial roles in determining the clinical course. However, the innate immune responses against SARS-CoV-2 remains poorly understood.
Here we showed that retinoic acid-inducible gene-I (RIG-I) but not MDA5 or TLR3 sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon(IFN)-independent manner. RIG-I inhibits viral RNA-dependent RNA polymerase (RdRp)mediated first step of replication through the preferential binding of RIG-I helicase do-

Figure 3.

main to the 3- untranslated region of the viral genomic positive-sense RNA. This new

The schematic representation of a novel defense mechanism of RIG-I for SARS-CoV-2

mode of RIG-I recognition fails to activate the conventional downstream MAVS/IPS-

RIG-I sufficiently restrains SARS-CoV-2 replication in epithelial cells without its canonicaldownstream pathway. Mechanistically, RIG-I inhibits viral RdRp-mediated replication
through the preferential binding of RIG-I helicase domain to the 3- untranslated region of
the viral genomic RNA. In RIG-I-reduced condition such as COPD, SARS-CoV-2 can replicate.
Re-expression of RIG-I by treatment with ATRA significantly suppresses viral replication.

1-dependent signaling, which is in accordance with lack of cytokine induction after
SARS-CoV-2 infection. Consistently, genetic ablation of RIG-I expression allows lungcells to produce viral particles. Furthermore, SARS-CoV-2 can replicate in chronic obstructive pulmonary disease (COPD) patient-derived cells with low levels of RIG-I ex-sion, significantly reduced viral titers in the cells. These data have defined RIG-I

pression. Treatment with all-trans retinoic acid (ATRA), which upregulate RIG-I expres-expression levels as one of the intrinsic determinants for the defense in human lungcells at least during the initial process of SARS-CoV-2 infection. It has been reported

Teaching Staff

that nearly 40-45% people infected with SARS-CoV-2 show asymptomatic with no robust upregulation of innate cytokines. In this respect, the balance between RIG-I expression levels and the amount of invading virus would regulate the fate of viral replication, which might determine cytokine responses and the related patient outcomes.
Selected Paper (2020.10-2022.5)

Lecturer

Seiichi SATO, Ph.D.

1. Y
 amada T, Sato S, Sotoyama Y, Orba Y, Sawa H, Yamauchi H, Sasaki M, Takaoka A.
RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells.
Nat Immunol. 2021 Jul; 22(7): 820-828.

Assistant professor

Taisho YAMADA, Ph.D.

2. B
 aidya S, Nishimoto Y, Sato S, Shimada Y, Sakurai N, Nonaka H, Noguchi K, Kido
M, Tadano S, Ishikawa K, Li K, Okubo A, Yamada T, Orba Y, Sasaki M, Sawa H,
Miyamoto H, Takada A, Nakamura T, Takaoka A. Dual Effect of Organogermanium
Compound THGP on RIG-I-Mediated Viral Sensing and Viral Replication during
Influenza a Virus Infection. Viruses. 2021 Aug 24; 13(9): 1674.

Staff
Professor

・・・・・・・・・・・・・・・・・・ Akinori TAKAOKA, M.D., Ph.D.

Lecturer

・・・・・・・・・・・・・・・・・・ Seiichi SATO, Ph.D.

3. K
 umar A, Mishra S, Kumar A, Raut AA, Sato S, Takaoka A, Kumar H. Essential roleof Rnd1 in innate immunity during viral and bacterial infections. Cell Death Dis.
2022 Jun 2; 13(6): 520

Assistant professor ・・・・・・・・・・・・・・・・・・ Taisho YAMADA, Ph.D.

13

Research Section of Molecular Pathogenesis

Division of Molecular Psychoimmunology

Professor Masaaki MURAKAMI, D.V.M., Ph.D.
Research Project

Regulation of chronic inflammatory diseases
by IL-6 amplifier and gateway reflex.
OutlineContents and Result

Since we discovered an unique inflammation-inducing

IL-6 amplifier

mechanism, called ‘IL-6 amplifier’ and ‘gateway reflex’, in2008 and 2012, respectively, we have investigated the

In 2008, we discovered ‘IL-6 amplifier’ as an inflamma-

molecular mechanisms of pathogenesis and exacerbation

tion-inducing mechanism underlying chronic autoimmune

in various inflammatory diseases. The ‘IL-6 amplifier’ is adiseases (Fig. 1): IL-6 amplifier is a molecular mechanism

mechanism for an excessive activation of NF-κB in non-to induce tissue-specific chronic inflammation by synergis-

immune cells, while the ‘gateway reflex’ is a moleculartically enhancing the production of inflammatory cyto-mechanism for development of tissue specific autoim-kines, chemokines and growth factors such as IL-6, TNF-

mune diseases via IL-6 amplifier at specific vascular sites

α, I L - 1 7 , C C L 2 0 , e p i r e g u l i n e , a n d E G F u p o n a

by activating neural circuit-mediated noradrenaline. Cur-simultaneous activation of NF-κB and STAT3 transcrip-

rently, we are organizing a research project on microin-tion factors in tissue-specific non-immune cells such as

flammation control in AMED Moonshot Goal 7, and con-synovial fibroblasts and tubular epithelial cells, as well as

duct research on the following five subjects inin ubiquitously present non-immune cells such as vascularcollaboration with Murakami’s laboratories at National In-

endothelial cells and fibroblasts. IL-6 amplifier is essential

stitute for Quantum and Radiological Science and Tech-for pathogenesis in mouse models of rheumatoid arthritis,

nology and National Institute of Natural Sciences, in ordermultiple sclerosis, graft rejection, and skin inflammation.

to establish ‘automatic medicine at the time of unwell-

In addition, we showed that approximately 1,700 positiveness’

regulators and target genes of IL-6 amplifier are deeply(i) IL-6 amplifier: analysis of the pathological roles of IL-6

involved in various chronic inflammatory diseases in hu-

amplifier in various inflammatory diseases such as infec-

mans through a functional screening of IL-6 amplifier-re-tious diseases and autoimmune diseases, and drug dis-lated genes in the whole genome and matching against

covery targeting IL-6 amplifier-regulating factors

the human disease-associated gene database. Indeed,(ii) Gateway reflex: analysis of the induction mechanism of

IL-6 amplifier was highly detectable in samples from pa-

gateway reflex-mediated autoimmune diseases by activa-

tients suffering from rheumatoid arthritis and multiple

tion of specific neural circuits

sclerosis, and its target molecules were found to present(iii) Quantum immunology: development of the detectionin the blood or urine of patients higher than in that ofsystem for perivascular microinflammation and tissue-

healthy individuals.

specific autoreactive T-cells

In recent years, Genome-Wide Association Study accom-(iv) Psychoneuroimmunology: analysis of the relationshippanied with a widespread use of next-generation se-

between mental/psychological states and immune re-quencing has demonstrated that disease-related genes

sponses based on stress gateway reflex and NPSLE modeland single nucleotide polymorphisms (SNPs) are geneti-(v) Space immunology: analysis of the mechanism of im-

cally associated with disease in a number of cases. We

munopathogenesis based on gravity gateway reflex andhave reported that molecules associated with these SNPs

space experimentsof the disease-susceptibility genes whose functions had

http://www.igm.hokudai.ac.jp/neuroimmune/index.html
14

Fig. 2: Gateway reflex
Six types of environmental stimuli (gravity, electric stimulation, pain,
chronic stress, light, and inflammation) cause or suppress (only lightstimulation) tissue-specific inflammatory diseases by triggering or
inhibiting (only light stimulation) IL-6 amplifier through an activation of
specific neural circuits for a vascular gate formation for autoreactive
T-cells to pass through the blood barrier into the CNS or retina. Thismechanism is called gateway reflex, which we have intensively studied.

Fig. 1: IL-6 amplifier
In tissue-specific non-immune cells such as synovial fibroblasts andtubular epithelial cells, as well as in ubiquitous non-immune cells such as
vascular endothelial cells and fibroblasts, cytokine stimulation-dependent
simultaneous activation of NF-κB and STAT3 pathways results in a local
synergistic enhancement of the production of inflammatory mediators.
The amplification of inflammation by IL-6 amplifier has been implicatedin the pathogenesis or exacerbation of various inflammatory diseases,
such as autoimmune diseases and cytokine storms that cause COVID-19
severity.

dent IL-6 amplifier activation in the dorsal vessels of fifth
lumbar spinal cord (L5), and facilitates the formation of avascular gateway for autoreactive CD4+ T cells to enter
the central nervous system (CNS) at blood brain barrier(BBB). This molecular mechanism can also be reproduced
by artificial electrical stimulations, in which electrical stimulation of muscles activates specific nerve circuits andnot yet been clarified, enhance or suppress inflammatory

promotes the vascular gateway formation at specific vas-

responses in keloids and Sjögren’s syndrome, etc, bycular sites in close vicinity of nerves (electric gateway re-positively or negatively modulating the activation of IL-6flex). Activation of neural circuits by pain sensation was

amplifier. In the future, we will contribute to public wel-also found to induce recurrent CNS inflammation by form-

fare by identifying novel diagnostic markers and drug tar-ing vascular gateways on the ‘ventral side’ of L5, different

gets through clarification of the molecular mechanisms

from the gravity-stimulated formation of gateways on the

how IL-6 amplifier’s target molecules and SNPs are asso-

dorsal side (pain gateway reflex). In 2017, we found that

ciated with the pathological conditions of autoimmune

even mild stress, which does not induce health damage,diseases such as rheumatoid arthritis, Dupuytren’s con-triggers microinflammation at specific blood vessels oftracture and systemic scleroderma, and infectious diseas-

brain in the presence of CNS-specific autoreactive T-cells

es such as COVID-19.

in the blood through an activation of stress-related neuralcircuits, which in turn induces abnormal activation of dormant neural circuits, leading to sudden death due to car-Gateway reflex

diac dysfunction (stress gateway reflex). On the other

The relationship between immune system and nervous

hand, studies using mouse model of uveitis (EAU) showedsystem has been so far studied in systemic regulation,that bright light stimulation reduced

named neuroendocrine-immune system including steroid

receptor expression in retinal vascular endothelial cells,

hormones. On the other hand, little is known about spe-

resulting in reduced IL-6 amplifier-mediated infiltration ofcific neuronal circuit-mediated the controlling of local im-

autoreactive T-cells into the retina and suppressing dis-mune responses. In early 2012, we discovered ‘gateway

ease onset (light gateway reflex). Furthermore, in 2022,

reflex’, a molecular mechanism, in which local neuronal

we found that gateway reflex also plays a role in diseases

circuit activation can alter specific vascular states via IL-6

characterized by symmetrical remote inflammation, such

amplifier, followed by the establishment of the gateways

as rheumatoid arthritis, where neurotransmitter ATP isfor immune cells in blood vessels (Fig. 2). We have re-produced upon IL-6 amplifier occurring in the unilateralported the gateway reflex triggered by six types of envi-

ankle joint, leading to a crosstalk between sensory nerveronmental factors and artificial neural stimulation. Our firstand interneuron. Ultimately, inflammation via IL-6 amplifi-

discovery was ‘gravity gateway reflex’, in which activation

er is also occurred in the contralateral ankle joint in ATP-of specific sensory-sympathetic circuits via gravitational

dependent manner (remote inflammation gateway reflex).

loading on soleus muscle triggers noradrenaline-depen-

As nervous and vascular systems run throughout body,15

α 1 noradrenergic

Fig. 3: Development of detection systems for tissue-specific autoreactive T-cells and therapies forperivascular microinflammation
In microinflammation control project on AMED Moonshot Goal 7, an ultra-sensitive detection
system will be developped utilizing quantum technologies, which can diagnose microinflammationin unwell state that is an ‘unaffected’ stage of disease, but could lead to chronic inflammation(e.g. immune disorders, dementia, and atherosclerosis) in the future. Furthermore, development ofneuromodulation technology will enable patient’s condition to be back from an unaffected state to ahealthy state by nipping the ‘disease bud (microinflammation)’.

the research on gateway reflex could explain pathogenic

autoreactive T-cell activation with ultra-high sensitivity, us-mechanisms of inflammatory diseases and mutual func-

ing highly sensitive quantum sensors including diamondtional regulation through organ connections in a view ofnanosensors. Furthermore, we will clarify how chronic in-neural circuit control.

flammation begins and progress, by examining the antigen
specificity of T-cell receptor on the AMED Moonshot R&D
projects (Fig. 3). We also aim at developing a technology,

Quantum immunology

which enables highly sensitive measurement of tissue-

Ageing and stress cause not only autoimmne diseases

specific autoantibodies produced by activated B cells bysuch as rheumatoid arthritis, but also metabolic syn-AI-nanopore techniques. Moreover, our AMED Moonshot

drome, dementia and other diseases related to chronic

R&D will create a neuromodulation technology to control

inflammation, which are inevitable in today’s ageing soci-the pathogenesis of various inflammatory diseases via vas-ety. Previous studies, including ours, have shown thatcular gateway by artificially inducing neural activation uti-chronic inflammation is caused by pathogenic immune

lizing the aforementioned gateway reflex mechanism.

cells-inducing microinflammation locally around specificblood vessels and invading various organs/tissues by

Psychoneuroimmunology

breaking through the vessels. However, no preventive
measures exist to detect and eliminate microinflammation

As the saying goes, ‘disease begins with the mind’, stressas a source of disease at an early stage. Through theis empirically known to attenuate organ functions andabove-mentioned our original and pioneering researchsometimes induce diseases. However, its molecular mech-

represented by ‘IL-6 amplifier’ and ‘gateway reflex’, weanism have not been clarified. Although there has been ahave come up with an idea that the measurement of mo-

vast amount of research on hormones and other humoral

lecular markers indicating ‘organ/tissue-specific activation

factors in organs innervated by nervous system, neuralof autoreactive T-cells’ and ‘inflammatory pathology oc-

circuits seemed to be directly related to the above prov-

curring around the vascular gateways’, would enable theerb. In 2017, we identified a stress gateway reflex mecha-

detection of microinflammation at a very early stage. In

nism, whereby chronic mild stress in the presence of au-

the future, we will visualize the location of microinflam-

toreactive T-cells that recognize myelin reduces

mation by detecting IL-6 amplifier and/or tissue-specificperipheral organ function and/or induces sudden death,16

by causing microinflammation (immune response) in spe-methods from a different perspective, which enable dis-cific blood vessels of the brain, followed by hyper-activat-

ease prevention and remission in the stressful society.

ing dormant neural circuits. By applying these findings andusing disease models, mainly in mice, we currently try toSpace immunology

clarify new gateway reflex mechanism induced by (1)stress and comfort states, or (2) direct stimulation/inhibi-

Gravity is a physical stimulus that cannot be avoided bytion of nerve nucleus involved in psychological and emo-

all terrestrial organisms, including humans, and it is there-tional regulation, and also to develop (3) biomarkers in-fore highly probable that there are response mechanisms

dicative of stress. As a result of these achievements, indirectly linked to biological functions that are evolution-

2022, we demonstrated that a part of the moleculararily important. We demonstrated that an increase or de-mechanism underlying the pathogenesis of CNS disordercrease in gravitational load defines the degree of disease

in systemic lupus erythematosus (SLE), called neuropsy-

pathogenesis in gravity gateway reflex mechanism inchiatric lupus (NPSLE) condition, is a stress-induced over-2012, by applying a tail suspension method in ground-

activation mechanism of brain neuronal circuits. Although

based experiments to reduce the gravitational load on thethe relationship between mental/psychological state al-hindlimbs of mice models of autoimmune diseases suchterations and pathological conditions is very complicate, if

as experimental autoimmune encephalomyelitis (EAE).

our research takes off, we expect to establish innovative

However, since the tail suspension method might causestress to the mice, due to unusual postures and restrictions on behaviors, and it was unclear how much whole-

Teaching Staff

body microgravity influences on inflammatory response of
the disease, we sent the mouse disease models induced
the autoimmune diseases to the International Space Station (ISS) for about a month in 2019. Now that they returned to the earth, we investigate what changes haveobserved in the lesion sites after exposure to microgravity

Associate Professor

Shintaro HOJYO, Ph.D.

Associate Professor

Shigeru HASHIMOTO, Ph.D.

conditions, comparing to ground control. Previous experi-

Specially Appointed Lecturer

Shimpei I. KUBOTA, M.D., Ph.D.

ence of astronauts in space has also indicated that prolonged exposure to space can cause vision loss, and thatthe space environment can also affect the optic nerve andretina. We have considered the possibility that these pathologies may also be related to gateway reflex caused
by light and gravity, and have conducted research using

Specially Appointed Lecturer

Yuta SHINOHARA, Ph.D.

Specially Appointed Lecturer

Jing Jing JIANG, M.D., Ph.D.

the mice returned from the ISS. We expect to create

Postdoctoral Researcher

space immunology field by clarifying how the space envi-

Rieko NISHI, M.D., Ph.D.

ronment alters the gateway reflex and inflammatory responses including IL-6 amplifier.

Postdoctoral Researcher

Noriyuki HIRATA, Ph.D.

Part-time Fellow

Kumiko TANAKA, Ph.D.

Selected Paper (2020.10-2022.5)
1. P
 athogenic neuropsychiatric effect of stress-induced microglial interleukin
12/23 axis in systemic lupus erythematosus.
Abe N, Tarumi M, Fujieda Y, Takahashi N, Karino K, Uchida M, Kono M,
Tanaka Y, Hasebe R, Kato M, Amengual O, Arinuma Y, Oku K, Sato W, Tha
KK, Yamasaki M, Watanabe M, Atsumi T, Murakami M., Ann Rheum Dis.
annrheumdis-2022-222566, 2022

Staff
Professor

・・・・・・・・・・・・・・・・・・ Masaaki MURAKAMI, D.V.M., Ph.D.

Associate Professor ・・・・・・・・・・・・・・・・・・ Shintaro HOJYO, Ph.D.
Associate Professor ・・・・・・・・・・・・・・・・・・ Shigeru HASHIMOTO, Ph.D.

2. A
 TP spreads inflammation to other limbs through crosstalk between sensory
neurons and interneurons.
Hasebe R, Murakami K, Harada M, Halaka H, Nakagawa H, Kawano F, Ohira Y,
Kawamoto T, Yull FE, Blackwell TS, Nio-Kobayashi J, Iwanaga T, Watanabe M,
Watanabe N, Hotta H, Yamashita T, Kamimura D, Tanaka Y, Murakami M., J
Exp Med. 219(6): e20212019, 2022

Specially Appointed Lecturer ・・・・・・・・・・・・・・・・・・ Shimpei I. KUBOTA, M.D., Ph.D.
Specially Appointed Lecturer ・・・・・・・・・・・・・・・・・・ Yuta SHINOHARA, Ph.D.
Specially Appointed Lecturer ・・・・・・・・・・・・・・・・・・ Jing Jing JIANG, M.D., Ph.D.
Postdoctoral Researcher ・・・・・・・・・・・・・・・・・・ Rieko NISHI, M.D., Ph.D.

3. R
 hodobacter azotoformans LPS (RAP99-LPS) Is a TLR4 Agonist That Inhibits
Lung Metastasis and Enhances TLR3-Mediated Chemokine Expression.
Murakami K, Kamimura D, Hasebe R, Uchida M, Abe N, Yamamoto R, Jiang
JJ, Hidaka Y, Nakanishi Y, Fujita S, Toda Y, Toda N, Tanaka H, Akira S, TanakaY, Murakami M., Front Immunol. 12: 675909, 2021

Postdoctoral Researcher ・・・・・・・・・・・・・・・・・・ Noriyuki HIRATA, Ph.D.
Part-time Fellow

・・・・・・・・・・・・・・・・・・ Kumiko TANAKA, Ph.D.

17

Research Section of Molecular Pathogenesis
Professor

Division of Hepatitis Virology

Kohji MORIISHI, D.V.M., Ph.D.

Research Project

Elucidation of the mechanisms of infection with
hepatitis B and C viruses and the pathogenesis of related liverdiseases and study on development of novel antiviral strategies
Outlinevaccines against hepatitis B virus. In addition, research on

Hepatitis B and C viruses are thought to be the cause ofvelop novel antiviral agents for COVID-19 therapy

SARS-CoV-2 is also being conducted to discover and de-more than half of the approximately 30,000 liver cancer

through the development of viral replicons.

deaths in Japan each year. Although the development ofantiviral drugs has made it possible to eliminate hepatitis

Contents and Result

C virus, problems such as hepatocarcinogenesis and re-

Elucidation of the mechanisms of hepatitis virus
replication and pathogenesis.

infection remain after HCV elimination. On the other
hand, although antiviral agents that are reverse transcriptase inhibitors are available as current hepatitis B therapy,

Caused by the hepatitis B virus (HBV), hepatitis B is bothcomplete elimination of the viral genome is not accom-a blood-borne and sexually transmitted disease and canplished due to cccDNA formation and host genome inser-

lead to hepatocellular carcinogenesis but not liver steato-tion, and the development of new antiviral agents is stillsis. Hepatitis C caused by hepatitis C virus (HCV), on therequired. There is also a need for new hepatitis B vaccine

other hand, is associated with liver steatosis and fibrosis,

development for reasons such as the inability of someeventually leading to hepatocellular carcinoma. Hepatitis

populations to induce sufficient immunity. Our aims are to

C is also known to be correlated with type 2 diabetes, in-elucidate the mechanisms of infection and virulence ofsulin-resistance. It is also known to be made more severeboth viruses and to develop novel antiviral agents andby coinfection with HBV and HCV. Thus, liver disorders

Fig. 1

https://www.med.yamanashi.ac.jp/clinical_basic/microbio/Microbiology_Yamanashi_Uni_Japanese/About_us.html
18

caused by HBV and HCV are not the same, but have theirown characteristics. Currently, cultured cell systems susceptible for infections with both viruses are technicallylimited, which is an obstacle to the development of new
antiviral agents and vaccines and to the elucidation of themechanisms of pathogenesis. In our laboratory, we are
analyzing the mechanisms of pathogenicity induction
through the development of monoinfected or coinfected
cell lines and model animals and the identification of hostfactors essential for their infections and pathogeneses.

Development of antivirals against hepatitis B
virus

Fig. 2

Hepatitis B virus (Hepatitis B virus) enters the human hepatocyte via the receptor NTCP, the viral genome is transported into the nucleus where it becomes cccDNA andinitiates stable viral genome replication. sgRNA is transported into the viral capsid and transcribed into relaxed
circular DNA by the reverse transcriptase activity of viral
polymerase in the nucleocapsid. Current antivirals used inclinical practice are derived from anti-HIV agents as reverse transcriptase inhibitors in origin. Therefore, cccDNA
and viral genome inserted into host genome could not becompletely eliminated from the patients. Our aims ofstudy are to develop antivirals that target infection steps
other than reverse transcription.

Development of HCV-surrogate animal models
using rodent hepaciviruses.

Fig. 3Since hepatocarcinogenesis is often observed after elimination of HCV from patients with hepatitis C by antiviral
agents, it is needed to elucidate the mechanism of hepa-

dent hepaciviruses, which are closely related to HCV andtocarcinogenesis by the virus and to develop new thera-can be used to infect immune-competent rats and mice.

pies. In addition, it is not uncommon for patients to be-

These surrogate models will be served as very usefulcome re-infected after elimination of HCV with antiviraltools for basic research for analysis on hepatitis C patho-

agents. Therefore, it should be necessary to develop vac-

genicity and vaccine development against HCV.

cines for developing countries and drug users. Experimental animal systems are required for pathogenicity analysis
and vaccine development. However, HCV has a very limited host range and is susceptible only to humans andchimpanzees. Human liver chimeric mice, which are susceptible for in vivo infection, are available as small experimental animals, but their immunodeficiency makes them
unsuitable for pathological and immunological analyses.
We are developing experimental animal models using ro-

Selected Paper (2020.10-2022.5)
1. T anaka T, Saito A, Suzuki T, Miyamoto Y, Takayama K, Okamoto T, Moriishi
K: Establishment of a stable SARS-CoV-2 replicon system for application in
high-throughput screening. Antiviral Res , 199: 105268, 2022:
2. T anaka T, Okuyama-Dobashi K, Motohashi R, Yokoe H, Takahashi K,
Wiriyasermkul P, Kasai H, Yamashita A, Maekawa S, Enomoto N, Ryo
A, Nagamori S, Tsubuki M, Moriishi K: Inhibitory effect of a novel
thiazolidinedione derivative on hepatitis B virus entry. Antiviral Res , 194:105165, 2021:

Staff

3. O
 toguro T, Tanaka T, Kasai H, Kobayashi N, Yamashita A, Fukuhara T, Ryo
A, Fukai M, Taketomi A, Matsuura Y, Moriishi K: Establishment of a Cell
Culture Model Permissive for Infection by Hepatitis B and C Viruses. HepatolCommun ,Professor ・・・・・・・・・・・・・・・・・・ Kohji MORIISHI, D.V.M., Ph.D.

19

Research Section of Pathophysiology
Professor

Division of Immunobiology

Ken-ichiro SEINO, M.D., Ph.D.

Research Project

Basic medical research for cancer andtransplantation/regeneration
mune regulatory strategy using pluripotent stem cells, andOutlineso on.

In this laboratory, we are interested in cancer and transplantation/regeneration, because Prof. Seino used to be aContents and Result

surgeon and involve in treating those diseases. Regarding
established, and it is expected that they are used for theDevelopment for new immune regulatory therapy
using pluripotent stem cells

donor source for transplantation (so called regenerative

Recently, it has been expected that pluripotent stem

medicine). We pursue basic medical research for cancer

cells are used for the donor source for cellular transplan-and transplantation/regeneration, aiming to discover ba-

tation. On the other hand, little attention has been paid to

sic phenomena and principles which may contribute to

immunological issues including allogeneic rejection. We

establish new diagnoses and therapeutics. Particularly, we

have tried to establish a novel immune-regulatory strategy

perform immunological research which is important forbased on the potential of pluripotent stem cells. So far,both cancer and transplantation. Our main research tar-

we have differentiated myeloid cells from mouse ES cells

gets are enhancement of immunity against cancer, rela-and further induced them to immune-suppressive regula-tionship between cancer stem cells and immunity, im-tory macrophages in the presence of several physiologicaltransplantation, pluripotent stem cells have been recently

Induction of immune regulatory macrophages from pluripotent stem cells and its application

https://seinolab.wixsite.com/seinolab/
20

active substances. When these regulatory macrophages

Importance of IL-34 produced by cancer cells

were administered to recipient mice which received allogeneic cellular transplants originally derived from the ES

We have recently found that chemoresisntant cancer

cells, significant prolongation of the graft survival was ob-

cells produce IL-34 which calls immune suppressive M2

served.

macrophages. In addition, They express CSF-1R and ac-

Recently, we have developed a mouse transplantation

cept the signal of IL-34, in turn increase AKT signal thenmodel in which MHCs are matched but minor antigens

help their own survival. In fact, in mice, when IL-34 was

are mismatched. Using this model, we can investigate de-inhibited, tumor growth became slow. We will further in-

tailed mechanisms in PSC-using transplantation.

vestigate whether similar function of IL-34 is observed inother cancer cells.

These results open new insights to develop new strate-

Recently, we have found that there are many MDSC ingy for safe and effective immune therapy in the allogeneic

IL-34 positive tumor. The MDSC induce angiogenesis andtransplantation using pluripotent stem cells.

Treg infiltration. We found that the regulation of MDSC
could improve the IL-34 induced therapy resistance ofcancer.

The pathological role of IL-34

Teaching Staff

Selected Paper (2020.10-2022.5)
1. R
 yo Otsuka, Haruka Wada, Ken-ichiro Seino. IL-34, the rationale of its expressionin physiological and pathological condition. Seminars in Immunology, 54: 101517
April 2021.
https://doi.org/10.1016/j.smim.2021.101517
Associate Professor

Haruka WADA, Ph.D.

Assistant Professor

2. N aoki Hama, Takuto Kobayashi, Nanumi Han, Fumihito Kitagawa, Nabeel
Kajihara, Ryo Otsuka, Haruka Wada, Hee-kyung Lee, Hwanseok Rhee, Yoshinori
Hasegawa, Hideo Yagita, Muhammad Baghdadi, Ken-ichiro Seino. Interleukin34limits the therapeutic effects of immune checkpoint blockade. iScience, 23: 10,2020 Oct 23.https://doi.org/10.1016/j.isci.2020.101584

Nanumi HAN, Ph.D.

Staff
Professor

・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・ Ken-ichiro SEINO, M.D., Ph.D.

3. T omoki Murata, Haruka Wada, Ryo Otsuka, Airi Sasaki, Hyuma Tsuji, Mizuho
Itoh, Nanami Eguchi, Tatsuo Kawai, Ken-ichiro Seino. Establishment of anexperimental model for MHC homo-to-hetero transplantation. Scientific Reports
10: 13560, 2020 Aug 11.https://doi.org/10.1038/s41598-020-69784-4

Associate Professor ・・・・・・・・・・・・・・・・・・ Haruka WADA, Ph.D.
Assistant Professor ・・・・・・・・・・・・・・・・・・ Nanumi HAN, Ph.D.

21

Research Section of Pathophysiology
Professor

Division of Genome Biology

Ken-ichi NOMA, Ph.D.

Research Project

Study on 3D genome organization and related diseases
Outlineand cohesin, mediate 3D genome organization. Condensin and

The eukaryotic genome is organized in the nucleus as a com-chromosomal compaction and sister-chromatid cohesion, re-cohesin complexes are known to play pivotal roles in mitotic

plex 3D genome structure that participates in various nuclear

spectively. Using state-of-the-art genomic technologies such as

events such as transcriptional regulation, DNA replication, andin situ Hi-C and ChIA-PET, we have shown that condensin andrepair. Disruption in the organization of the genome structure

cohesin participate in 3D genome organization. Interestingly,

correlates with human diseases, including cancer. Despite thecondensin and cohesin direct different gene contact networks,

clear importance of 3D genome organization to basic and medi-

although they are distributed at approximately 500 gene locical research, the function and mechanism of 3D genome organi-across the fission yeast genome and often bind to the samezation remain unclear. Our laboratory employs genomic, genetic,

gene loci. For instance, condensin organizes 300-500 kb large

cell biological, and biochemical approaches to study 3D genome

chromatin domains, while cohesin forms 30-50 kb smaller do-organization in fission yeast and human cells. The research proj-

mains (Figure 1; Kim et al. Nature Genetics 2016; Tanizawa etects currently underway are:al. Nature Structural & Molecular Biology 2017).
Mechanistically speaking, we have found that condensin di-

Study with the fission yeast model

rectly interacts with the TATA-box binding protein TBP, a gener-・Understand how 3D genome organization participates

al transcription factor (Iwasaki et al. Mol Cell 2015). TBP recruits

in transcriptional regulation and chromosome dynamics

condensin onto highly transcribed genes across the genome,・Elucidate the molecular mechanisms that form and regu-

and condensin molecules localized at dispersed gene regions, inlate 3D genome structures throughout the cell cycle

turn, mediate 3D genome organization. Therefore, our study im-・Uncover proteins and their post-translational modifica-plies that condensin is the molecular link that connects genomewide gene expression patterns with 3D genome organization.

tions involved in 3D genome organization

Since condensin and cohesin are widely conserved among eu-

Research on human senescencekaryotes, 3D genome-organizing mechanisms investigated in the・Determine how 3D genome organization contributes tofission yeast model are potentially present in higher eukaryotes.

transcriptional regulation in senescent cells

Please see the following section for our human study.

・Elucidate how 3D genome structure is formed and regu-

Elucidation of 3D genome organization and gene
regulation in human senescent cells

lated in senescent cells
・Uncover proteins involved in 3D genome organization in

In addition to the fission yeast model, our laboratory studies

senescent cells

3D genome organization in human cells. Our current research
focuses on understanding how 3D genome structure is formed

Contents and Result

and regulated in senescent cells. Cellular senescence is defined

Elucidation of the 3D genome-organizing mechanism in the fission yeast model

as a state of stable cell-cycle arrest and serves as an intrinsic
defense against abnormal cell proliferation associated with ev-

Our laboratory employs fission yeast as a model system to

ery type of cancer. It is known that senescence is accompanied

elucidate mechanisms of 3D genome organization. In particu-

by reorganization of the 3D genome structure. Senescent pro-lar, we are interested in how protein complexes, condensin

cesses also involve the global reprogramming of gene expres-https://www.igm.hokudai.ac.jp/3dgenome/ja/index.html
22Figure 1. Model of 3D genome organization by condensin and cohesin

Figure 2. Gene contact maps for human chromosome 4 in OIS (top right)
and growing cells (bottom left)sion. Especially genes encoding the senescence-associated secretory phenotype (SASP) factors are highly activated uponsenescence; SASP factors include interleukins, chemokines,
growth factors, and matrix metalloproteinases. Using the latest
genomic method (in situ Hi-C), we have determined the 3D genome structure in Oncogene-Induced Senescence (OIS) cells.
Our genomic study has shown that heterochromatin domains
cluster in OIS cells, as previously observed by a microscopic
approach (Figure 2). Interestingly, we also found that the key
genome-organizing machinery, condensin, participates in senescent processes (Yokoyama et al. Cell Cycle 2015; Iwasaki et al.
Nature Communications 2019). Our future project aims to elucidate how condensin concomitantly mediates 3D genome organization and transcriptional regulation in senescent cells.

Figure 3. Finding of novel chromosomal axial protein BAZ1B using
comprehensive proteomics

Elucidating mitotic chromosome architectureusing advanced proteomics

during the formation of mitotic chromosomes. This framework

Chromosomal condensation is an essential process for thehas been suggested to correspond to an insoluble biochemical

proper segregation of the genome during mitosis and meiosis,

fraction and referred to as the chromosome scaffold, although

and its abnormalities are linked to human diseases such as can-how chromosome condensation during mitosis occurs via thecer and hematological disorders. We have employed a mass

formation of the chromosome scaffold remains unclear.

spectrometric-based proteomics approach to understanding

Using a quantitative proteomics approach, we have recently

how the chromosomal architecture during mitosis is organizeddetermined the protein composition of the chromosome scaf-

by various factors (Ohta et al. Cell 2010; Curr Opin Cell Biolfold (Ohta et al. Mol Cell Proteomics 2019). We have found that

2011; Mol Cell Proteomics 2016). A classic model proposes that

BAZ1B is one of the most concentrated proteins in the scaffold
fraction and is indeed located on the chromosomal axis (Figure

non-histone chromatin proteins act as a structural framework3). Knockouts of BAZ1B and its homolog BAZ1A result in aberrant chromosomal condensation during mitotic prophase. Our

Teaching Staff

study suggests that BAZ1A and BAZ1B are a part of the chromosome scaffold and required for chromosome condensation
around early mitosis. I will continue to use advanced proteomics tools to investigate how the interphase genome andmitotic chromosomes are organized.

Associate Professor

Shinya OHTA, Ph.D.

Selected Paper (2020.10-2022.5)
1. S akuno T, Tashiro S, Tanizawa T, Iwasaki O, Ding DQ, Haraguchi T, Noma K*,
Hiraoka Y. (2022) Rec8 cohesin-mediated loop-axis chromatin architecture isrequired for meiotic recombination. Nucleic Acids Research. 2022 March 25;
On line doi: 10.1093/nar/gkac183

Staff
Professor

・・・・・・・・・・・・・・・・・・

Ken-ichi NOMA, Ph.D.

Associate Professor ・・・・・・・・・・・・・・・・・・ Shinya OHTA, Ph.D.

*Co-correspondence

23Research Section of Pathophysiology
Professor

Division of Developmental Physiology

Fumio MOTEGI, Ph.D.

Research ProjectMechano-chemical crosstalk in control ofbiological asymmetry
Outlineand differentiation. Coordination between cell differentiation and proliferation during development requires the

Cell polarity, establishment of spatial asymmetry within abalance between asymmetric and symmetric modes ofcell, is necessary for diverse processes in living organisms.

cell division. However, the cellular intrinsic cue underlying

Dedicated polarity proteins generate and maintain cellu-

the choice between these two division modes remains

lar asymmetry, leading to establishment of functional ar-

elusive. Here we show evidence in Caenorhabditis ele-chitecture in many types of cells. Despite the conservedgans that the invariable lineage of the division modes isrole of polarity proteins, a fundamental question remains

specified by the balance between antagonizing complex-

unanswered: How do developmental cue(s) break cellular

es of partitioning-defective (PAR) proteins. By uncoupling

symmetry during embryogenesis? How is a group of cells

unequal inheritance of PAR proteins from that of fate de-arranged into organ architectures?

terminants during cell division, we demonstrate that

Our group is interested in understanding the mechanics

changes in the balance between PAR-2 and PAR-6 can beof spatial patterning of cellular asymmetry. A simple mod-sufficient to re-program the division modes from symmet-

el system, Caenorhabditis elegans nematode, provides

ric to asymmetric and vice versa in two daughter cells.

the unique opportunity to explore such procedures in cell

The division mode adopted occurs independently ofpolarization, as the embryos undergo“de novo ”polariza-

asymmetry in cytoplasmic fate determinants, cell-sizetion with stereotypical spatio-temporal kinetics. We areasymmetry, and cell-cycle asynchrony between the sister

also using mammalian cultured cells and tissues to inves-

cells. We propose that the balance between PAR proteinstigate the conserved cell polarity circuits. By taking multi-

represents an intrinsic self-organizing cue for the specifi-

disciplinary approach with genetics, biochemistry, bio-

cation of the two division modes during development.

physics, and modern imaging technology, our group aims
insights into how a developing embryo commits to estab-

Genetic suppressors for loss-of-cell-polarity mutant animallish diverse cell fates and tissue shapes with precision and

Loss of cell polarity is a hallmark of cancer, neurodegen-to delve into the basic principles of cell polarity and yieldaccuracy. The molecular similarity of C. elegans to othereration, and ageing. To acquire medical implication andsystems including human makes it very likely that thisenhance therapeutic opportunities, our group aims toproject will highlight highly conserved mechanisms andidentify new targets that can prevent progression of cell-

lead to insights into asymmetric division in stem cells, pre-polarity-related diseases. We used C. elegans as a model

vention of cancer, and tissue regeneration.

system to identify genetic suppressors of the conserved
polarity kinase, PAR-1. Therapeutic treatments should

Contents and Result

minimize potential side effects by themselves, but the ge-

A balance between antagonizing PAR proteins specifies the pattern of asymmetric and symmetric divisions

can be difficult to identify by traditional genetic screen-

netic lesions associated with undetectable phenotypes
ings. Recent advancement of whole-genome sequencing

The development of a multicellular organism requires(WGS) makes screening for genetic suppressors as astrict control of the balance between cell proliferation

powerful and cost-effective method. We took a combina-

https://www.motegilab.com
24Lineage of cellular patterning in C. elegans embryogenesis

Microtubules (green) and focal adhesions (magenta) in a humanfibroblast celltion of WGS with single nucleotide polymorphism (SNP)
mapping to simultaneously map and sequence mutants
generated by mutagenesis. We have isolated 24 independent suppressor mutations, which allow par-1(zu310) ani-eral types of formins from different species. In experi-mals viable at the restrictive temperature 25℃. These

ments with cultured fibroblasts, we found that SMIFH2

suppressor mutations were mapped by WGS-SNP ap-

inhibits retrograde flow of myosin 2 filaments and con-proach and validated their suppressor activity by RNAi

traction of stress fibers. We further checked the effect of

method. Among the suppressors, three intragenic muta-

SMIFH2 on non-muscle myosin 2A and skeletal muscle

tions in the par-1 gene activate PAR-1 kinase activity. We

myosin 2 in vitro and found that SMIFH2 inhibits myosin

are currently investigating how other suppressor muta-

ATPase activity and ability to translocate actin filaments intions can suppress lethality and infertility of the par-the in vitro motility assay. While inhibition of non-muscle

1(zu310) mutant animals.

myosin 2A in vitro required a higher concentration of
SMIFH2 than inhibition of retrograde flow and stress fiber

The formin inhibitor SMIFH2 inhibits the memberof myosin superfamily

contraction in cells, inhibition of several other non-muscle
myosin types, e.g. mammalian myosin 10, Drosophila my-

The small molecular inhibitor of formin FH2 domains,osin 7a and Drosophila myosin 5 by SMIFH2, was equally

SMIFH2, is widely used in cell biological studies. It wasor more efficient than inhibition of formins. Since actin po-

selected in a chemical screen as a compound inhibiting

lymerization and myosin contractility are linked in many

formin-driven actin polymerization in vitro , but not polym-

cytoskeleton processes, additional careful analysis iserization of pure actin, and found to be active against sev-

needed in each case when function of formins was proposed solely on the basis of experiment with SMIFH2.

Teaching Staff

Lecturer

Kenji KIMURA, Ph.D.

Selected Paper (2020.10-2022.5)

Assistant Professor

1. L
 im YW, Wen FL, Shankar P, Shibata T, Motegi F. (2021) A balance between
antagonizing PAR proteins specifies the pattern of asymmetric and symmetriccell divisions in C. elegans embryogenesis. Cell Reports. 36, 109326.

Yukako NISHIMURA, Ph.D.

2. N
 ishimura Y, Shi S, Zhang F, Liu R, Takagi Y, Bershadsky AD, Viasnoff V, andSellers JR. (2021) The Forming Inhibitor, SMIFH2, Inhibits Members of the
Myosin Superfamily. J Cell Sci, 134, jcs253708.

Staff
Professor

・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・ Fumio MOTEGI, Ph.D.

Lecturer

・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・
・ Kenji KIMURA, Ph.D.

3. P
 asapera AM, Heissler SM, Eto M, Nishimura Y, Fischer RS, Thiam HR, Waterman
CM. (2022) MARK2 regulates directed cell migration through modulation of
myosin II contractility and focal adhesion organization. Current Biology. doi.
org/10.1016/j.cub.2022.04.088

Assistant Professor ・・・・・・・・・・・・・・・・・・ Yukako NISHIMURA, Ph.D.

25

Research Section of Pathophysiology
Associate Professor

Division of Microbial Oncology

Naoko KAMIYA, Ph.D.

Research Project

Molecular mechanism underlying
Helicobacter pylori -mediated gastric carcinogenesis
Outlineknown as MARK2) via CM motif in a tyrosine phosphoryla-

Gastric cancer is the third leading cause of cancer death inpolarity defects. H. pylori has been thought to promote neo-

Japan, where nearly 50,000 people die of gastric cancer ev-

plastic transformation of gastric epithelial cells via CagA-de-tion-independent manner, thereby causing junctional andery year. It has now been well established that chronic infec-

pendent deregulation of cell signaling (Figure 1). However, H.

tion with Helicobacter pylori (H. pylori ) is associated with thepylori eradication cannot reduce the risk of gastric cancer indevelopment of gastric cancer. In 2014, the International

patients with precancerous intestinal metaplasia, indicating

Agency for Research on Cancer (IARC), a division of thethat H. pylori is no longer required for the later phase of gas-

World Health Organization (WHO), reported that 78% of all

tric carcinogenesis.

gastric cancer cases are estimated to be attributable toIn this study, we found that CagA impairs nuclear accumu-

chronic H. pylori infection. Especially, infection with H. pylori

lation of BRCA1 in a CM motif-dependent manner. Mechanis-

strains carrying a gene called cagA plays an essential role intically, CagA/PAR1b interaction inactivates PAR1b and there-

gastric carcinogenesis. The cagA -positive H. pylori delivers

by inhibits PAR1b-dependent phosphorylation of BRCA1 on

the cagA gene product, the CagA protein, into the host gas-

Ser616 that is required for cytoplasmic-to-nuclear transloca-

tric epithelial cells via the type IV secretion system. Althoughtion of BRCA1 (Figure 2). The breast/ovarian tumor suppres-H. pylori has been thought to promote neoplastic transfor-

sor BRCA1 that has essential functions in homologous re-mation of gastric epithelial cells via CagA-dependent deregu-

combination (HR), a high-fidelity mechanism to repair DNA

lation of cell signaling, whole molecular mechanism of gastricdouble-strand breaks (DSBs), is also important in the protec-

carcinogenesis is yet to be understood. East Asian countries

tion of stalled replication forks.“BRCAness”is defined by aincluding Japan are known to show the highest incidence of

defect in HR-mediated DSB repair by inactivated mutation ofgastric cancer in the world. Thus, establishment of new strat-

BRCA1 -related genes. CagA-induced shortage of nuclear

egies for prevention and treatment for gastric cancer is ur-

BRCA1 causes replication fork instability leading to DSBs that

gently required. In our division, we are conducting cutting-are repaired through error-prone pathways such as non-ho-edge researches to elucidate oncogenic mechanisms of themologous end joining (NHEJ).

bacterial CagA protein. These researches will provide an opportunity to develop molecular-targeting methods that effectively prevent the development of gastric cancer.

Contents and Result
Helicobacter pylori CagA elicits transient BRCAness to promote gastric carcinogenesis
Chronic infection with cagA -positive H. pylori plays a criticalrole in the development of gastric cancer. Inside the humangastric epithelial cells, CagA undergoes tyrosine phosphorylation by host cell kinases (Figure 1). Tyrosine-phosphorylated CagA acquires the ability to specifically bind to and acti-

Figure 1. Deregulation of host cell signaling by H. pylori CagA

vate SHP2 tyrosine phosphatase, causing aberrant activation

In human gastric epithelial cells, CagA interacts with SHP2 in a tyrosine
phosphorylation-dependent manner, thereby activating its phosphataseactivity. On the other hand, CagA interacts with PAR1b in a tyrosine
phosphorylation-independent manner, thereby inhibiting its kinase activity.

of the Ras-Erk signaling pathway. CagA binds and inhibits thepolarity-regulating serine/threonine kinase PAR1b (also26

Figure 2. H. pylori CagA elicits transient BRCAness in gastric epithelial cells.

Figure 3. Pathogenic effects of cagA -positive H. pylori infection in mouseand human gastric epithelial cells.

PAR1b-dependent phosphorylation of BRCA1 on Ser616 is required forcytoplasmic-to-nuclear translocation of BRCA1. CagA inhibits nuclear
translocation of BRCA1 via PAR1b inhibition, thereby inducing transient
BRCAness without mutations in BRCA1-related genes.

Due to the incompatible interaction between H. pylori HopQ and mouse
Ceacam1, there is no or little delivery of CagA in the mouse gastricepithelial cells. In contrast, compatible binding of H. pylori HopQ tohuman CEACAM1/5 leads to efficient delivery of CagA in human gastricepithelial cells leading to CagA-mediated carcinogenesis.

DSBs are the most dangerous types of DNA damage, inducing apoptosis. The CagA/PAR1b interaction also stimulates

of induction of gastric cancer in mice with long-term cagA -Hippo signaling and thereby circumvents DSB-triggered

positive H. pylori infection. In contrast, transgenic expression

apoptosis. Furthermore, intermittent expression of CagA inof CagA in mice gave rise to the spontaneous development

cultured cells, which mimics CagA delivery in the H. pylori -of malignancies including gastric cancer. These findings rasecolonized human stomach, induces somatic mutations withthe possibility that cagA -positive H. pylori cannot deliver

BRCAness-associated COSMIC signatures, Signature 3 andCagA into mouse gastric epithelial cells.

ID6, indicating that CagA elicits transient BRCAness. Genome

We conducted an in vitro infection experiment using mouseinstability caused by CagA-induced transient BRCAness may

gastric epithelial cell lines, YTN2 and YTN16 cells. Mousepromote acquisition of additional driver gene mutations that

gastric epithelial cells resist CagA delivery by cagA -positive

confer H. pylori -independence in terms of neoplastic trans-

H. pylori , as expected. To test whether impairment of CagA

formation (Imai et al. Cell Host Microbe 2021).

delivery into mouse gastric epithelial cells by H. pylori wasdue to the weak interaction of H. pylori HopQ and mouse

Mouse gastric epithelial cells resist CagA delivery
by Helicobacter pylori

Ceacam1, we established transfectant cells stably expressing
human CEACAM1, CEACAM5, or CEACAM6 using YTN2 and

The initial step in bacterial infection is adherence of theYTN16 cells. Ectopic expression of human CEACAM1 orbacterium to the target cell surface. H. pylori exploits the in-

CEACAM5 in mouse gastric epithelial cells made it possibleteraction of bacterial adhesin protein HopQ with humanfor cagA -positive H. pylori to deliver CagA into the cells.

CEACAMs expressing on the surface of gastric epithelial

Thus, cagA -positive H. pylori cannot deliver CagA into mouse

cells, which is necessary for delivery of the CagA into the ep-

gastric epithelial cells via the type IV secretion system due toithelial cells via type IV secretion system. It has been report-

the absence of HopQ-Ceacam interaction (Figure 3). In othered that H. pylori HopQ binds to human CEACAM1,

words, even though mice are routinely used for H. pylori in-

CEACAM5, and CEACAM6. In contrast to human CEACAMs,

fection studies, mouse is thought to be an inappropriate

H. pylori HopQ does not interact with mouse Ceacam1. Be-

model for studying the role of H. pylori CagA in gastric carci-cause the mouse genome lacks Ceacam5 and Ceacam6

nogenesis (Shrestha et al. Int. J. Mol. Sci. 2022).

genes, H. pylori may interact much less efficiency with mousegastric epithelial cells than with human gastric epithelial

Selected Paper (2020.10-2022.5)

cells.

1. S . Imai, T. Ooki, N. Murata-Kamiya*, D. Komura, K. Tahmina, W. Wu, A. TakahashiKanemitsu, C.T. Knight, A. Kunita, N. Suzuki, M. Tsuboi, M. Hata, Y. Hayakawa,
N. Ohnishi, K. Ueda, M. Fukayama, T. Ushiku, S. Ishikawa, M. Hatakeyama*.
Helicobacter pylori CagA elicits BRCAness to induce genome instability that may
underlie bacterial gastric carcinogenesis. Cell Host Microbe , 29, 1-18, 2021.
*Co-corresponding authors.

Mice have been used in many studies for artificial infection
with H. pylori . Although infection of mice with cagA -positive
strains gave rise to more severe mucosal damage than infection with cagA -negative strains did, there has been no report

2. K olinjivadi AM, Sankar H, Choudhary R, Tay LS, Tan TZ, Murata-Kamiya N, Voon
DC, Kappei D, Hatakeyama M, Krishnan V, Ito Y. The H. pylori CagA oncoprotein
induces DNA double strand breaks through Fanconi Anemia pathway
downregulation and replication fork collapse. Int. J. Mol. Sci. , 23, 1661, 2022.

Staff

3. S hrestha R, Murata-Kamiya N, Imai S, Yamamoto M, Tsukamoto T, Nomura
S, Hatakeyama M. Mouse gastric epithelial cells resist CagA delivery by the
Helicobacter pylori type IV secretion system. Int. J. Mol. Sci. , 23, 2492, 2022.

Associate Professor ・・・・・・・・・・・・・・・・・・ Naoko KAMIYA, Ph.D.

27

Research Section of Disease Control
Professor

Division of Functional Immunology

Toru KONDO, Ph.D.

Research ProjectControl of immunological function and its application to
immunotherapy for infectious disease, cancer, allergy, and autoimmune diseases.
Outlinetherapy targeting neuro-immune conducting cells to augment cancer malignancy. In addition, we conduct immune

Immune system, composed of various immune cells, ismonitoring for patients and try to identify useful biomark-essential to maintain our health. Both Type 1 and Type 2

er to establish novel cancer immunotherapy in collabora-

immunity is tightly controlled because excessive activa-tion with Hokkaido University Hospital and Graduatedtion may cause a lot of immune diseases such as autoim-

School of Medicine.

mune, allergy and tumorigenesis. Therefore, the proper
regulation of the ‘immunological function’ is critical for

Imbalance of T cell- and dendritic cell-mediated immune

prevention and therapy of the immune diseases. We havestatus becomes the cause of various immune-related dis-scientifically clarified the precise mechanisms in the oc-

eases including infectious disease, cancer and allergy.

currence of the diseases using our originally established

Nowadays, it is essential to identify accurate biomarkers

animal disease models. In this laboratory, pivotal roles ofto evaluate immune status of individuals. Recent studies

regulation for the immunological function by T cells andhave indicated that microRNA, short non-cording RNAs,

dendritic cells have been investigated in order to apply

can become a promising biomarker for prediction of ma-

the findings to development of novel immunotherapy for

lignancy or life expectancy of cancer patients. Therefore,

infectious disease, cancer, allergy, and autoimmune diseases. We also aim to contribute to society through ourbasic and translational studies in collaboration with Hokkaido University Hospital and Graduated School of Medicine.

Contents and Result
Research on function of dendritic cells and its application to
immunotherapy for infectious disease, cancer and allergy
Dendritic cells (DCs) are one of the most powerful antigen-presenting cells to activate T cell-mediated immune
responses. One goal of our research is to develop a novel
immunotherapy through functional control of antigen-specific helper T and killer T cells in addition to DCs. The related research subjects are as follows; (a) Induction of tu-

Fig. 1. Neuropeptide signaling through NK2R augments cancer
malignancy in tumor microenvironment.

mor-specific T cells by regulation of DC function and its
application to tumor immunotherapy; (b) Regulation

Use of receptor antagonists blocking neuropeptide signaling pathwaythat are caused by viral or bacterial infection, chronic inflammation, andstress, may prevent cancer malignancy in tumor microenvironment.

mechanism of cancer immunity by NKA-NK2R-mediatedneuropeptide signaling in chronic inflammation including
infection and allergy; (c) Development of novel immuno-

http://www.igm.hokudai.ac.jp/funimm/
28

Fig. 3. Effects of IL-6 on anti-tumor immunity in tumor microenvironment.

Fig. 2. Proper regulation of individual immune status is crucial for safeand effective vaccination and therapy.

IL-6 produced in the tumor hosts suppresses antitumor immunity
involving the activation of effector T cells and dendritic cells. Lack of IL-6
facilitates cancer immunotherapies using immune checkpoint inhibitors
and immunological adjuvants.

Evaluation of microRNA is a promising strategy for checking individual
immune status. Furthermore, the functional miRNA may be a powerfultool for the proper regulation.

we investigated the usefulness of serum microRNA as anovel biomarker for precise evaluation of immune status
in immunotherapy. These findings also suggest that microRNA will become a useful biomarker for prediction andevaluation of immune responses in various diseases suchas infections disease, allergy, atopy, infection in addition
to the personalized cancer immunotherapy.
Immunosuppression in tumor microenvironments is oneof the critical issues for cancer immunotherapy. To create
more effective treatment, it is essential to overcome thedysfunction of immunity in cancer patients. We have demonstrated that IL-6, a pleiotropic cytokine, significantly inhibited maturation of murine and human dendritic cells(DCs) via STAT3 activation. In this study, we investigate
the effects of IL-6 produced under tumor microenvironments or chronic inflammation on antigen-presenting ability of DCs. These findings suggest that IL-6/STAT3 signaling causes dysfunction of DCs, which will be a promisingtarget for improving the effects of cancer immunotherapy.

Teaching Staff

Selected Paper (2020.10-2022.5)
1. X
 iang H, Toyoshima Y, Shen W, Wang X, Okada N, Kii S, Sugiyama K, Nagato T,
Kobayashi H, Ikeo K, Hashimoto S, Tanino M, Taketomi A, Kitamura H. IFN-α/β-mediated NK2R expression is related to the malignancy of colon cancer cells.
Cancer Sci . 2022 May 13. doi: 10.1111/cas.15397. in press.
2. O kada N, Sugiyama K, Shichi S, Shirai Y, Goto K, Sakane F, Kitamura H, Taketomi
A. Combination therapy for hepatocellular carcinoma with diacylglycerol kinasealpha inhibition and anti-programmed cell death-1 ligand blockade. Cancer
Immunol Immunother . 2022 Apr; 71(4): 889-903. doi: 10.1007/s00262-02103041-z.

Associate Professor

Hidemitsu KITAMURA, Ph.D.

Staff
Professor

3. K osaka A, Ishibashi K, Nagato T, Kitamura H, Fujiwara Y, Yasuda S, Nagata M,
Harabuchi S, Hayashi R, Yajima Y, Ohara K, Kumai T, Aoki N, Komohara Y, Oikawa
K, Harabuchi Y, Kitada M, Kobayashi H, Ohkuri T. CD47 blockade enhances theefficacy of intratumoral STING-targeting therapy by activating phagocytes. J Exp
Med . 2021 Nov 1; 218(11): e20200792. doi: 10.1084/jem.20200792.

・・・・・・・・・・・・・・・・・・ Toru KONDO, Ph.D.

Associate Professor ・・・・・・・・・・・・・・・・・・ Hidemitsu KITAMURA, Ph.D.

29

Research Section of Disease Control

Professor

Division of Molecular Interaction

Kazuma TANAKA, Ph.D.

Research Project

Physiological significance of phospholipid
asymmetry in biological membranes.
teins that regulate phospholipid asymmetry, focusing on

Outlineelucidating the molecular basis underlying the phospho-

In most cell membranes of eukaryotic cells, phospholipid

lipid asymmetry. We use the yeast Saccharomyces cerevi-

compositions are different between two monolayers. Thissiae as a model organism, which is amenable to studies inasymmetrical distribution of phospholipids is calledmolecular genetics, cell biology, and biochemistry. We are“phospholipid asymmetry”(Fig. 1). This phospholipid

promoting the following projects.

asymmetry is observed in internal membranes as well as
in the plasma membrane, and is involved in various cellContents and Result

functions, including cell polarity, membrane trafficking andRoles of membrane phospholipid asymmetry in theestablishment of cell polarity and vesicular trafficking

organelle functions. Since phospholipid asymmetry is observed in most cell membranes, its perturbation seems to
be involved in various pathological states. Phospholipid

We found that phospholipid flipping by flippases playasymmetry is generated, maintained, and regulated byimportant roles in the establishment of cell polarity andlipid translocation or flip-flop across membranes, but pro-vesicular trafficking, especially in vesicle formation on theteins involved in this flip-flop need to be clarified. Type 4early endosome in the endocytic recycling pathway (Fig.

P-type ATPases or flippases are one such protein and2). We will elucidate the molecular mechanism in thistheir functions should be elucidated to know physiologi-

flippase-mediated vesicle formation. We will also investi-

cal significance of phospholipid asymmetry.

gate the role of flippases in the integrity of Golgi membranes.

Our laboratory is interested in the identification of pro-

Fig. 1. Phospholipid asymmetry and phospholipid flippases
Asymmetric distribution of phospholipids in the plasma membrane is a general feature in eukaryotic
cells. Generally, phosphatidylcholine and sphingomyelin are primarily present in the exoplasmic
leaflet, whereas phosphatidylserine and phosphatidylethanolamine are in the cytosolic leaflet.
Phospholipid flippases that catalyze the transport of lipid molecules from the exoplasmic tocytosolic leaflet play an important role in establishing and maintaining the phospholipid asymmetry.
Changes in phospholipid asymmetry by flippases regulate cell polarity and vesicle trafficking.

https://www.igm.hokudai.ac.jp/molint/
30

Isolation and analysis of Cfs1 that antagonistically functions to flippases
We identified the Cfs1 gene as a mutation that suppresses the growth defects of flippase mutants. For example, the neo1 flippase mutant is lethal, but the neo1
cfs1 double mutant grows like wild-type cells. These results suggest that Cfs1 antagonistically functions to flippases. Cfs1 is a membrane protein localized to the Golgi
apparatus. It might function as a scramblase, which allows

Fig. 2. Abnormal membrane structures found in flippase mutant cells

random translocation of phospholipids, but we need toElectron microscopic observation demonstrated that abnormal
membrane structures were accumulated in the flippase mutant. These
structures, which are not observed in the wild-type cells, appear to beaccumulated early endosomal membranes due to defects in vesicle
formation from early endosomes.

further investigate its function (Fig. 4).

A novel plasma membrane protein Sfk1 regulates
phospholipid asymmetry
We are also promoting the identification of novel proteins involved in the regulation of phospholipid asymmetry. We isolated Sfk1 and our results suggest that Sfk1
suppresses both flip and flop of phospholipids (Fig. 3).
We are now investigating the molecular mechanisms ofmode of action of Sfk1. Recently, we found that phospho-

Fig. 4. A model for the mode of action of Cfs1

lipid flippases and Sfk1 are essential for the retention ofBecause Cfs1 was isolated as a suppressor mutation of flippase
mutations, it seems to antagonistically function to flippases. It might
function as a scramblase, but further investigations are required.

ergosterol (sterols in fungi) in the plasma membrane.

Fig. 3. A model for the mode of action of Sfk1
We propose that Sfk1 regulates phospholipid asymmetry by suppressing
phospholipid flip and flop.

Teaching Staff

Selected Paper (2020.10-2022.5)

Assistant Professor

Takuma KISHIMOTO, Ph.D.

1. C
 haracterization of micron-scale protein-depleted plasma membrane
domains in phosphatidylserine-deficient yeast cells.
Mioka T, Guo T, Wang S, Tsuji T, Kishimoto T, Fujimoto T, Tanaka K.
J Cell Sci. 2022 Mar 1; 135(5): jcs256529. doi: 10.1242/jcs.256529.

Staff
Professor

2. P hospholipid flippases and Sfk1 are essential for the retention ofergosterol in the plasma membrane. Kishimoto T, Mioka T, Itoh E,
Williams DE, Andersen RJ, Tanaka K. Mol Biol Cell. 2021 Jul 15; 32(15):1374-1392. doi: 10.1091/mbc.E20-11-0699.

・・・・・・・・・・・・・・・・・・ Kazuma TANAKA, Ph.D.

Assistant Professor ・・・・・・・・・・・・・・・・・・ Takuma KISHIMOTO, Ph.D.

31

Research Section of Disease Control

Professor

Division of Biomedical Oncology

Masahiro SONOSHITA, Ph.D.

Research Project

Elucidating the mechanisms of cancer development
to develop novel cancer therapies
hibitor sorafenib, which has very strong side effects in pa-

Outlinetients.

Cancer is currently the leading cause of death in Japan.

First we performed a chemical genetic screening for all

Despite advances in research, effective treatments are still

kinases in the kinome of MTC model flies, and found that

limited. Therefore, our laboratory aims to develop novel

inhibition of MNK1, BRAF, and others is an ‘undesirable

cancer therapies by elucidating the fundamental process-inhibition’ causing toxicity for sorafenib. We named thesees of cancer development. Here we will introduce our re-kinases ‘anti-targets’ to avoid while treatment

cent advances.

Computational chemistry then predicted an analog ofsorafenib that, by increasing the size of a portion ofContents and Result

sorafenib, would continue to bind to Ret as a desirable

Establishing novel methods to generate anticancer drugs

analog to mice implanted with human MTC, it produced

target, but not to the anti-targets. When we dosed thissignificantly improved tumor suppression over sorafenib.

Drugs can be one of the effective tools in the fightThus, by combining fly genetics with computational

against cancer. In recent years, ‘targeted therapy’, which

chemistry, and mammalian experimental systems, ouraims to reduce the side effects of drugs by targeting mol-laboratory has succeeded in creating novel leads with re-ecules specifically present in cancer, has been actively

duced side effects of existing drugs through ‘Rational

studied. However, it has become clear that even ap-

polypharmacology’ (Figure 1; Sonoshita & Cagan. Currproved cancer drugs still have serious side effects and are

Top Dev Biol 2017; Sonoshita et al. Nat Chem Biol 2018).

not as effective as expected.

The key in this study was that flies allowed comprehen-

To solve this issue, our laboratory has been taking mul-

sive and rapid whole body analyses. We expect to apply

tiple approaches for drug discovery that complement thethis method to study also other diseases where drug dis-concept of targeted therapy. As one of the methods, ourlaboratory focused in particular on existing approved
drugs and gradually modify their structures to enhancetheir anticancer effects while maintaining their pharmacokinetics, such as absorption, distribution, metabolism, andexcretion, when administered orally.
We have been using the fruit fly Drosophila to model
patients' genotype. This is because flies offer a convenientresearch toolkit with many advantages to complement
mammalian models. For example, flies have a high degreeof conservation of genes and signaling pathways with humans, a wealth of genetic tools for whole body analyses,

Figure 1: Rational polypharmacology. Based on anti-targets of existing
drugs identified by fly chemical genetics, derivatives are generated
by computational chemistry. Their widened therapeutic window is
confirmed in mammals to create a new anticancer lead.

and reduced costs for production and breeding. As a drug
model, on the other hand, we chose the multi-kinase in-https://bmoncology.wixsite.com/mysite
32

covery has been problematic.

Elucidating the pathogenesis of pancreatic cancer to develop new treatments
One of the most difficult cancers to treat is pancreaticcancer. The number of deaths due to pancreatic cancer is
expected to continue to rise, and it is projected toemerge as the second leading cause of cancer death by2030. However, the development of new drugs to treat
pancreatic cancer has been extremely difficult, mainly due
to the lack of new therapeutic targets and the lack of ex-

Figure 2: A novel pancreatic cancer research platform combining
Drosophila and mammals in a complementary manner. We generate
flies that mimic genotype of pancreatic cancer patients, and use theseflies in a genetic screening to identify novel therapeutic targets. Then,compounds that inhibit these targets are screened out and evaluated fortheir efficacy in model mice.

perimental models to efficiently evaluate new seeds.
To tackle this problem, we have recently created a novel animal model in flies that mimics genotype of patients
carrying pancreatic cancer. We found that the model flies
exhibited tumor phenotypes such as increased cell proliferation and motility, and animal lethality. We then per-to create novel animal models of pancreatic cancer, aformed a comprehensive genetic screening using thesetypical intractable cancer, and to identify novel therapeu-

flies to identify genes and signaling pathways that pro-tic targets and drug candidates (Figure 2: submitted, in-mote or suppress these phenotypes. In this analysis weternational patent pending). Based on these results, our

specifically examined the function of kinases, which play alaboratory is currently engaged in the generation of mod-role in relaying, amplifying, and branching signals in vari-

el flies that mimic various cancer genotypes, the elucida-ous signaling pathways. As a result, we found that thetion of the mechanisms of these cancers, and the creationthese traits were suppressed when activity of several ki-

of novel therapeutics using these model flies.

nases including MEK was reduced. These results suggestthat these kinases are candidates for novel therapeutictargets in pancreatic cancer.
Therefore, we focused on approved drugs and experimental inhibitors of these kinases and administered thesecompounds to a mouse model xenografted with humanpancreatic cancer. Consequently, these compounds markedly inhibited tumor formation in mice. Analysis of clinicalspecimens also confirmed the presence of these novel
therapeutic targets in pancreatic cancer tissue in patients.
These results indicate that it is possible to employ flies

Teaching Staff

Assistant Professor

Takako OOSHIO, Ph.D.

Assistant Professor

Ryodai YAMAMURA, Ph.D.

Staff
Professor

・・・・・・・・・・・・・・・・・・ Masahiro SONOSHITA, Ph.D.

Selected Paper (2020.10-2022.5)

Assistant Professor ・・・・・・・・・・・・・・・・・・ Takako OOSHIO, Ph.D.

1. Yamamura R*, Ooshio T*, Sonoshita M. (2021). Tiny Drosophila makes
giant strides in cancer research. Cancer Science 112(2): 505-514. (*equal
contribution)

Assistant Professor ・・・・・・・・・・・・・・・・・・ Ryodai YAMAMURA, Ph.D.

33

Research Section of Disease Control

Professor

Division of Biological Molecular Mechanisms

Nobuo N. NODA, Ph.D.

Research Project

1. Research on the molecular mechanism of autophagy
2. Research on biological phenomena regulated by liquid-liquid phase separation
3. Structure-based studies of biomolecular mechanisms
OutlineContents and Result

Autophagy is a major intracellular degradation system

Mechanism of Autophagy Regulation by LiquidLiquid Phase Separationand contributes to the health of the organism through thedegradation of toxic substances such as damaged mito-

Liquid-liquid phase separation of proteins and nucleic

chondria, denatured proteins, and invasive bacteria. Au-

acids plays diverse functions in cells through the forma-tophagy performs degradation by sequestering degrada-tion of membraneless organelles (liquid droplets). We

tion targets into the newly formed double-membranefound that the pre-autophagosomal structure (PAS), whichorganelle called autophagosome and transporting themserves as a site for autophagosome formation, is a liquid

to lysosomes. We are (1) utilizing structural biology tech-droplet formed by the liquid-liquid phase separation ofniques to obtain the structure and clues to molecular

Atg proteins. Furthermore, we succeeded in reconstitut-function of autophagy-related (Atg) proteins, (2) reconsti-

ing the PAS droplets in vitro and demonstrated that the

tuting and simplifying the various processes of autophagyliquid-liquid phase separation by dephosphorylation ofin vitro to understand the functions, and (3) performing

the intrinsically disordered protein Atg13 is responsible

cell-based assays to validate the findings obtained in vitro

for the initiation of autophagy through the formation ofand to extract physiologically significant functions andthe PAS (Nature 2020). Furthermore, we have shownphenomena. We are also analyzing the roles of liquid-liq-

through analysis of selective autophagy substrates in

uid phase separation, a physical phenomenon that is uni-

yeast that liquid-liquid phase separation not only regu-

versally observed in proteins, in the regulation of various

lates autophagy machinery but also affects the degrada-

biological phenomena, including autophagy, using thetion efficiency of the target proteins. From these studies,

methods described in (1) to (3) above.

we have also shown that liquid-liquid phase separation
enables efficient sequestration of substrate proteins into
autophagosomes by collecting them in droplets, and that

Figure 1: Regulation of autophagy machineries (left) and degradation targets (right) by liquid-liquid phase separation.

https://mechanism.igm.hokudai.ac.jp/
34Regulatory mechanism of autophagic membrane
dynamics by lipidated Atg8

sequestration is abolished when droplets become solid
due to mutation (Mol Cell 2020).

Atg8 is a ubiquitin-like protein that plays a central role in

Mechanism of autophagosomal membrane formation by lipid transport proteins

autophagosome formation by strongly binding to autophagy-associated membranes through enzymatic conjuga-

Autophagosome formation is an extremely importanttion to phospholipids. Despite its importance, the molecu-

process in autophagy that defines degradation substrates,

lar functions of lipidated Atg8 during autophagosome

but the mechanism by which new lipid membranes areformation are not well understood. We first analyzed theformed has long been a mystery. We found that Atg2, aeffect of lipidated Atg8 on membrane morphology using

protein that localizes at the expanding edge of the isola-

giant liposomes and found that lipidated Atg8 is active intion membrane (the precursor membrane of autophago-widening the area difference between two leaflets of asomes) and contacts the endoplasmic reticulum mem-

lipid bilayer membrane, resulting in a change in lipid

brane, has the activity to tether lipid membranes to eachmembrane morphology. Next, the conformation of lipi-

other and to transport lipids between the tethered mem-

dated Atg8 was studied by NMR, which revealed that lipi-

branes (Nat Struct Mol Biol 2019). Furthermore, we founddated Atg8 has a specific orientation with respect to thethat Atg9, a membrane protein localized at the expanding

lipid membrane and that two phenylalanine residues

edge of isolation membranes together with Atg2, has lipid(F77, F79) are in contact with the membrane. The alaninetransfer activity between the two layers of lipid bilayers

mutations of F77 and F79 in Atg8 resulted in a loss of(lipid scrambling activity) (Nat Struct Mol Biol 2020).

membrane morphogenetic activity and a significant de-

Based on these findings, we proposed a novel model ofcrease in the efficiency of autophagosome formation. In

membrane formation in which Atg2 tethers the endoplas-

conclusion, we demonstrated that lipidated Atg8 has the

mic reticulum to the isolation membrane and transports

activity to interact with lipid membranes and change theirlipids from the endoplasmic reticulum to the cytosolic

morphology, which enables efficient autophagosome for-leaflet of the isolation membrane, and Atg9 distributes

mation (Nat Struct Mol Biol 2021).

lipids from the cytosolic to the luminal leaflet to enable
isolation membrane expansion.

Figure 3: Proposed structure of lipidated Atg8 on the membrane (left)
and activity to induce membrane deformation (right).

Figure 2: Detection of lipid scramblase activity of Atg9 (left) andproposed model of isolation membrane expansion mediated by Atg2
and Atg9 (right).

Teaching Staff

Selected Paper (2020.10-2022.5)

Associate Professor

Yuko FUJIOKA, Ph.D.

Specially appointed
assistant professor

Daisuke NOSHIRO, Ph.D.

1. M
 atoba, K., Kotani, T., Tsutsumi, A., Tsuji, T., Mori, T., Noshiro, D.,
Sugita, Y., Nomura, N., Iwata, S., Ohsumi, Y., Fujimoto, T., Nakatogawa,
H., Kikkawa, M. and Noda, N. N. Atg9 is a lipid scramblase that mediates
autophagosomal membrane expansion. Nat. Struct. Mol. Biol. 27, 11851193 (2020). DOI: 10.1038/s41594-020-00518-w

Specially appointed
assistant professor

Yuta OGASAWARA, Ph.D.

2. K
 odera, N.#, Noshiro, D.#, Dora, S. K.#, Mori, T., Habchi, J., Blocquel,D., Gruet, A., Dosnon, M., Salladini, E., Bignon, C., Fujioka, Y., Oda, T.,
Noda, N. N., Sato, M., Lotti, M., Mizuguchi, M., Longhi, S. and Ando, T.
Structural and dynamics analysis of intrinsically disordered proteins byhigh speed atomic force microscopy. Nat. Nanotech. 16, 181-189 (2021).
DOI: 10.1038/s41565-020-00798-9 (#equally contributed)

Staff
Professor

・・・・・・・・・・・・・・・・・・ Nobuo N. NODA, Ph.D.

Associate Professor

・・・・・・・・・・・・・・・・・・ Yuko FUJIOKA, Ph.D.

3. M
 aruyama, T., Alam, J. M., Fukuda, T., Kageyama, S., Kirisako, H.,
Ishii, Y., Shimada, I., Ohsumi, Y., Komatsu, M., Kanki, T., Nakatogawa,H. and Noda, N. N. Membrane perturbation by lipidated Atg8 underlies
autophagosome biogenesis. Nat. Struct. Mol. Biol. 28, 583-593 (2021).
DOI: 10.1038/s41594-021-00614-5

Specially appointed assistant professor ・・・・・・・・・・・・・・・・・・ Daisuke NOSHIRO, Ph.D.
Specially appointed assistant professor ・・・・・・・・・・・・・・・・・・ Yuta OGASAWARA, Ph.D.

35

Frontier Research Unit

Associate Professor

Molecular Cell Biology

Tomohiko OKAZAKI, Ph.D.

Research Project

Understanding the cell fate determination by
post-translational modifications and inter-organelle communications,and the interactions between immune and nervous systems
OutlineOur research goal is to understand how cells integrate
numerous external and internal signals into meaningful biological outputs by focusing on (1) post-translational
modifications and logistics of proteins, or (2) inter-organelle communications. In addition, we are also studying (3)the interactions between immune and nervous systems
and (4) neuroethology using Drosophila. Through thesestudies, we wish to discover the sophisticated systems ofliving organisms for surviving in a complex world.

Contents and Result
Host defense mechanisms against pathogen
infection
When mammalian cells get infected with viruses, they
activate the innate immune system as a first-line defense
mechanism before activating the adaptive counterpart.
The RIG-I-like receptor family, which detects virus-derived

ciently remove the infecting virus. However, it remained

RNA within infected cells, and its adaptor molecule IPS-1/

unclear whether such differential regulation exists within

MAVS play central roles in this innate immune system.

infected cells and, if it does, how it is controlled. Our lab-

IPS-1 is mainly localized on the mitochondrial outer mem-oratory has identified novel modifications and binding

brane and has been known to trigger host defense mech-molecules of IPS-1 to address this question.

anisms including type I interferon (IFN) production andcell death (apoptosis). Type I IFN inhibits viral replication

Protein carboxylation

within infected cells, and apoptosis of infected cells altruistically prevents viral propagation to surrounding cells.

Protein functions are regulated not only by its amino

Although both strategies appear to be effective means ofacid sequence but also by various post-translational mod-suppressing viral replication, ironically they can also be

ifications. Among them, protein carboxylation is a rare but

harmful to the host organism in some instances. There-

unique post-translational modification in which a carboxyl

fore, it is reasonable to assume that host cells may regu-

group are added to glutamate and aspartate residues bylate use of the two mechanisms to optimize the benefit toa γ-carboxylase GGCX in a vitamin K (VK) dependent

the organism in a context dependent manner and effi-manner. To date, about 20 substrates have been identi-

https://www.igm.hokudai.ac.jp/molcell/
36

fied as GGCX substrates, which regulate limited physio-

being addressed worldwide as new paradigm shift. We

logical processes including blood coagulation and bone

have discovered novel interactions between mitochondria

formation. We are now examining whether this protein

and peroxisomes, and between mitochondria and stresscarboxylation plays any role in the regulation of immune

granules, and found that these interactions may play im-

systems.

portant roles in cell physiology (Tanaka et al., Journal of
Cell Science, 2019; Aoyama et al., Journal of Immunology,2021). We are further investigating the role of these inter-

Inter-organelle communicationsorganelle communications.

Although organelles have been long assumed to performstudies have discovered functional coordination between

The interactions between immune and nervous
systems in health and disease

them through inter-organelle communications, which is

The central nervous system has long been thought as antheir unique functions by their own organizations, recent

immune-privileged site having no direct communicationand interaction with the immune system at least underhealth conditions, due to its functional importance andthe structural features of the blood-brain barrier. However, recent studies have revealed (rediscovered) the presence of lymphatic vessels (pathways for immune cells) inthe brain, and also the presence of various immune cells
in the adult brain through scRNA-seq analysis. Furthermore, it has been also shown that immunodeficient mice,
which lack both T cells and B cells, exhibited various behavioral abnormalities, indicating that immune cells play
crucial role in the formation of neural circuits and thebrain function. We are currently investigating which andhow immune cells contribute to the pathogenesis (or alleviation) of viral infections in the brain, neurodegenerative diseases, and psychiatric disorders such as autism
and schizophrenia.

Teaching Staff

Assistant Professor

Selected Paper (2020.10-2022.5)

Nao MORIMOTO, Ph.D.

1. A
 oyama-Ishiwatari S, Okazaki T *, Iemura S, Natsume T, Okada Y, Gotoh Y.
NUDT21 links mitochondrial IPS-1 to RLR-containing stress granules andactivates host antiviral defense. Journal of Immunology . (2021), DOI: https://doi.org/10.4049/jimmunol.2000306 (*Corresponding Author)

Staff
Associate Professor ・・・・・・・・・・・・・・・・・・ Tomohiko OKAZAKI, Ph.D.

2. O
 nda M, Takeuchi R, Isobe K, Suzuki T, Masaki Y, Morimoto N, Osakada F.
Temporally multiplexed dual-plane imaging of neural activity with fourdimensional precision. Neuroscience Research . (2021), https://doi.org/10.1016/
j.neures.2021.02.001

Assistant Professor ・・・・・・・・・・・・・・・・・・ Nao MORIMOTO, Ph.D.

37

Endowed Department

Professor

Department of Synbiotics

Tadaaki MIYAZAKI, Ph.D.

Research Project

To study the functional roles of synbiotics and to apply
these results in prevention and treatment of infectious diseases, cancer and autoimmune diseases
OutlineWe study the functions and roles of probiotics, prebiotics and synbiotics in the human immune system and thenaim to apply our study results in prevention and treatment of infectious diseases, cancer and immune diseases,
allergies. Probiotics refers to foods or products which include microbes and their components; metabolites (suchas lactic-acid, acetic acid or propionic acid) which areconsidered to improve human health; and bifidobacterium, saccharifying bacteria, natto bacteria, clostridium butyricum and yeast. Dr. Ilya Mechnikov, who had worked in
Pasteur Laboratory, is well known for his groundbreaking
research about the white cell blood phagocytosis. He focused on the longevity of the people in Bulgaria, investigating the correlation between longevity and lifestyle. Afterwards, he proposed that lactic-acid bacteria (which isfound in yoghurt) is useful for human longevity. It has
been revealed that lactic-acid bacteria control the intestinal-tract immune system and are effective in the prevention of infectious diseases, hay fever, allergies, inflammatory bowel disease, cancer, many lifestyle-related

Figure 1

diseases and obesity. Prebiotics such as oligosaccharides,
induce the growth or enhance the activity of beneficial
microorganisms and contribute to human health. Synbiot-

Contents and Result

ics are mixtures of probiotics and prebiotics, to increase

Effect of lactic acid bacteria and beta-glucan to
improve the allergic symptom

the beneficial microorganism have functions to maintainand enforce human health. Therefore, we aim to understand the molecular mechanism of the lactic-acid bacteria

Atopic dermatitis causes inflammation by overproduc-by identifying its constituents and clarifying their function-

tion of IgE antibodies associated with an immune re-al roles in the prevention and treatment of these diseas-sponse, and when the barrier function of the skin is re-es.

duced, antigens are more likely to invade from theoutside. In addition, it is accompanied by strong itching asa clinical symptom, which increases the burden and effort

http://www.igm.hokudai.ac.jp/pbi/
38

of daily life is great. Currently, no cure has been established, and symptomatic treatment is to relieve symptoms
to the extent that they do not interfere with daily life. Recent research has reported the possibility that the ingestion of lactic acid bacteria (LAB) and/or beta-glucan suppress IgE antibody production and relieve the symptoms
of atopic dermatitis. Therefore, using drug-induced dermatitis mice model, we evaluated the improvement effector prevention of dermatitis by the screened LAB (killed
LAB) and beta-glucan derived from Aureobasidium pullu-

lans , and found that these synbiotics are effective to improve the symptoms.

Effects of lactic acid bacteria to prevent the viral
infection and improve the symptom of influenza
The effects of prevention and symptom relief of influenza
virus infection were examined using the screened LAB

Streptococcus faecalis PCR strain (live or killed). The efficacy was judged by the change in body weight, which isthe standard for evaluation of the severity by viral infection in mice. As a result, suppression of weight loss wasobserved and it indicates that the LAB intake is effective
to prevent the viral infection. In addition, when the mechanism of the effects was investigated, the blood concentration of IFN-alpha was increased. There is no report that

Streptococcus faecalis is effective to prevent the infectionof influenza virus or improve the symptom by regulation of
immune response. Therefore, the purpose of this study is

Figure 2

to examine their reproducibility of the effects and clarify
the molecular mechanisms and to lead to the development of functional foods and drugs related to regulate theimmunity by the Streptococcus faecalis PCR strain.

Teaching Staff

Professor

Koichi SATO

Assistant Professor

Kazunobu BABA, S.C., Ph.D.

Staff
Professor

・・・・・・・・・・・・・・・・・・ Tadaaki MIYAZAKI, Ph.D.

Selected Paper (2020.10-2022.5)

Professor

・・・・・・・・・・・・・・・・・・ Koichi SATO

1. T
 adaaki Miyazaki, Koichi Sato, Takashi Shimada, Masanori Kurimoto, Hiroyo
Kagami-Katsuyama, Clinical study to verify the effects of Ganoderma lucidum
to activate NK cell-A placebo-controlled, randomized, double-blind, parallel-groupcomparative study-, Jpn Pharmacol. Ther., vol. 50, no. 4, 2022

Assistant Professor ・・・・・・・・・・・・・・・・・・ Kazunobu BABA, S.C., Ph.D.

39

Attached Facility

Laboratory of Animal Experiments

Director (Professor)

Kenichiro SEINO, M.D., Ph.D.

Research Project

Promotion of humane care and use of experimental
animals in high-quality research
OutlineThis laboratory was established in April 2000 as ashared facility of the Institute for Genetic Medicine, withthe aim of conducting animal experiments with high accuracy and reproducibility. Its predecessor was the Laboratory of Animal Experimentation of Institute of Immunological Science which was established in 1976. In April 2008,
a completely renovated facility was opened, and serviceof reproductive technology has started. All animal experiments conducted at this facility have to be properly conducted from the viewpoint of scientific and animal welfare
according to the National University Corporation Hokkaido University Provisions on Animal Experiments. Currently,
inbred and genetically engineered mice are used in thefacility. In addition to a general animal room, the facility
has a BSL3/ABSL3 room, anti-cancer drug use laboratory,a laboratory for reproductive technology for mice, a quarantine room, etc. Furthermore, as devices registered in
the Hokkaido University Open Facility, we have a non-invasive High-sensitivity in vivo imaging of fluorescence andbioluminescence system (IVIS Spectrum), an X-ray CT
scanner for small animals, and an X-ray irradiation device.

http://www.igm.hokudai.ac.jp/lae/index-j.html
40

Fig. 1. Equipment in the facility 1
A: Air conditioning systems. B: Double-door barrier autoclaves. C: SPF animal room. D:
Biosafety level 3 room (BSL3/ABSL3) for animals experimentally infected with highly
virulent microbes.

Fig. 2. Equipment in the facility 2
E: IVIS® Imaging Systems. F: X-ray μCT. G: Anti-cancer drug use room. H: Germ cellmanipulation room for generate genetically engineered mice.

Selected Paper (2020.10-2022.5)

Teaching Staff

1. S
 uzuki, R.; Yamasoba, D.; Kimura, I.; Wang, L.; Kishimoto, M.; Ito, J.;
Morioka, Y.; Nao, N.; Nasser, H.; Uriu, K.; Kosugi, Y.; Tsuda, M.; Orba,
Y.; Sasaki, M.; Shimizu, R.; Kawabata, R.; Yoshimatsu, K.; Asakura, H.;
Nagashima, M.; Sadamasu, K.; Yoshimura, K.; Genotype to Phenotype
Japan, C.; Sawa, H.; Ikeda, T.; Irie, T.; Matsuno, K.; Tanaka, S.;
Fukuhara, T.; Sato, K., Attenuated fusogenicity and pathogenicity of
SARS-CoV-2 Omicron variant. Nature 2022, 603, (7902), 700-705
2. M
 uthusinghe, D. S.; Shimizu, K.; Lokupathirage, S. M. W.; Wei, Z.;
Sarathkumara, Y. D.; Fonseka, G. R. A.; Senarathne, P.; Koizumi, N.;
Kawakami, T.; Koizumi, A.; Wickramasinghe, C.; Ebihara, H.; Matsuno,
K.; Tsuda, Y.; Arikawa, J.; Gamage, C. D.; Yoshimatsu, K., Identificationof Novel Rodent-Borne Orthohantaviruses in an Endemic Area of Chronic
Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka. Viruses 2021,
13, (10), 1984

Associate Professor

Kumiko YOSHIMATSU, D.V.M., Ph.D.

Staff

3. Yasuda, S. P.; Shimizu, K.; Koma, T.; Hoa, N. T.; Le, M. Q.; Wei, Z.;
Muthusinghe, D. S.; Lokupathirage, S. M. W.; Hasebe, F.; Yamashiro,
T.; Arikawa, J.; Yoshimatsu, K., Immunological Responses to Seoul
Orthohantavirus in Experimentally and Naturally Infected Brown Rats
(Rattus norvegicus). Viruses 2021, 13, (4), 665

Director (Professor) ・・・・・・・・・・・・・・・・・・ Kenichiro SEINO, M.D., Ph.D.
Associate Professor ・・・・・・・・・・・・・・・・・・ Kumiko YOSHIMATSU, D.V.M., Ph.D.

41

Attached Facility

Research Center for Infection-associated Cancer /Joint Usage・Research Center Promotion Office

PI, Professor

Masahiro SONOSHITA, Ph.D.

Research Project(1) Gene expression analysis of cervical cancer virus(HPV)-positive infected cancers followed by
identification of preventive and therapeutic target molecules(2) Analysis of the role of cytokine signals in COVID-19 progression(3) Role of H. pylori in the development of gastric cancer

OutlineProfessor Noma (Development of New Technology).

The“Center of infection-associated Cancer”introduced

laboratory in 2022. Professor Moriishi (cross appointment

here is an affiliated facility of Institute for Genetic Medicine

with the University of Yamanashi) is working on hepatitis vi-

In addition, three infectious cancer researchers joined the(IGM). The former Center with the same name, which con-ruses, Professor Hatakeyama (cross appointment with theducted research on infectious cancer induction, and theInstitute for Microbiology and Biochemistry) is working on H.

Joint Usage/Collaborative Research Promotion Office, which

pylori, and independent Associate Professor Kamiya is also

was established to promote the center’s projects, were in-

conducting research on H. pylori. The Center has laborato-

tegrated and streamlined as the“Center for Infectious Can-ries, including the P2 laboratory on the 5th floor of the insti-

cer Research”. The purpose of the center is to conducttute, the P3 laboratory in the animal facility, and super-reso-

world-class research on infectious cancer by promoting ex-lution confocal microscopes and other equipments forchanges and collaboration with domestic and international

collaborative research with researchers in the field of infec-

researchers. Furthermore, an“IGM-Liaison Laboratory”was

tious diseases and cancer. The following three experiments

established within the Center of infection-associated Cancer

are performed as the institute projects in this Center. (1)in 2017 to reinvigorate this the Joint Usage/Collaborative

Joint research with Hokkaido University Hospital, with the

Research project. The Liaison Laboratory is composed of

aim of developing new prevention and treatment methods

five virtual laboratories, each of which divides the process offor several types of cancer, including HPV-positive infected

infectious cancer induction into the four categories of infec-

cancers. (2) Analysis of the role of cytokine signals in COV-

tion, oncogenesis, immune response, and inflammation in-

ID-19 progression. Furthermore, (3) hepatitis viruses and in-duction, and adds the field of new technology development,

fectious cancers, and (4) H. pylori and infectious cancers are

to promote and develop the fusion of different research

being studied.

fields, promote joint research with academic institutions andIn addition, there are four administrative tasks of the Joint

companies at home and abroad, promote research. The

Usage/Integrated Research Center project that are carried

center also promotes joint research with domestic and for-out by this research center as follows.

eign academic institutions and companies, intellectual prop-(1) Recruitment, selection, and implementation of joint re-erty of research results, and symposiums to create a hub forsearch and joint research meetings for the MEXT’s Joint re-a new community of researchers, and to return research re-search/ Collaborative Research Project“Center for Infec-

sults to society and disseminate information. The respective

tious Cancer”: Research that is promoted by researchers

fields are led by Professor Takaoka (Infection), Professor

from both inside and outside the university who apply for 15

Kondo (Carcinogenesis), Professor Seino (Immune Re-

proposals submitted by IGM researchers on research lead-sponse), Professor Murakami (Inflammation Induction), anding to the prevention and treatment of infectious cancers

https://www.igm.hokudai.ac.jp/vec/
42

and emerging infectious diseases. The Collaborative Re-seas research groups and academic conferences on infec-

search Program, in which proposals are reviewed and imple-

tious cancer, and support for the operation of the Hokkaido

mented, is the core project of the Center for Infectious Can-

University Cross-Divisional Symposium, an intramural projectcer Research. Collaborative research includes generalto support young researchers: With funds donated by Dr.

collaborative research, in which researchers apply for re-

Ichiro Azuma, a former director of IGM, young researchers insearch and travel expenses to visit the Center or send spec-

each field are encouraged to participate in overseas re-imens to conduct research using advanced research equip-

search groups and academic conferences on infectious can-ment, and budding collaborative research, in whichcer, which are conducted by young researchers from theirresearchers apply for research samples and postal expenses

respective departments. Since 2016, the cross-divisional

for delivery of preliminary data as a preliminary step to ap-

symposium of Hokkaido University has been hosted by IGM.

plying for general collaborative research. As for research

In 2021, when the symposium was held on the web due tomeetings, the MEXT’s Joint research/ Collaborative Re-

the SARS-CoV-2 disaster, it was held in October with more

search Project Symposium on“Infection, Immunity, Cancer,

than 750 participants from 36 departments in the university

and Inflammation”is held every year as a research meeting

under the subtitle of“Creation of Fusion Research by Young

directly related to“Advanced Research on Infectious Cancer

Researchers”.

Caused by Persistent Bacterial and Viral Infection,”and(4) Countermeasures against SARS-CoV-2 infections: The

three to four times a year, researchers of the Institute pro-Center also provides support for the preservation of re-pose to obtain major research grants. We will also support

search materials and analysis of the pathogenesis mecha-

efforts to obtain 3-4 large research grants proposed by ournisms of emerging infectious diseases caused by SARS-

institute’s researchers each year, or to expand the number

CoV-2, which are conducted by the Institute’s hygieneof such grants after they are obtained. In addition, the cen-laboratory authorized by Sapporo City. In addition, the insti-

ter will manage and operate the common equipment usedtute is implementing a support program to store research

for the research in the center’s projects.

materials such as cell lines, mouse fertilized eggs, and sperm(2) Support for the operation of the IGM-Liaison Laboratory:

free of charge for researchers who are unable to conduct

Five virtual laboratories, or liaison laboratories, each consist-research in the midst of SARS-CoV-2 disaster. In addition,

ing of four sections of the process of cancer induction: infec-

the institute is conducting research to elucidate the molecu-

tion, carcinogenesis, immune response, and inflammation in-lar mechanism of cytokine storm induction, which is theduc tion, a s w ell a s the fiel d o f ne w t e chnol o g ymechanism of severity of new coronavirus infection, anddevelopment. The Liaison Labs were organized in 2017, andmemory T cell analysis for vaccine development, mainly

each lab is headed by a professor of the IGM, who con-through the Institute’s internal health laboratories.

ducts joint research with other facilities, including domestic
and foreign universities and companies that conduct related

Contents and Result

research. In particular, as for the development of new technologies, a next-generation sequencer was introduced in(1) Gene expression analysis of human papillomavirus

2020, and a“Genome Analysis Laboratory”is being estab-(HPV)-positive infected cancers to differentiate subtypes oflished to conduct genome analysis and gene expression

cervical cancers

analysis as a commissioned project in the future.

In 2018, approximately 570,000 people worldwide were

(3) Support for young researchers in IGM and outside ofdiagnosed with cervical cancer and about 310,000 people
died from the disease. About 99% of cervical cancers are

IGM: Support for young researchers to participate in over-

infected cancers caused by high-risk HPV infection; vaccines exist for HPV, which have suppressed high-risk HPV
infection worldwide and reduced the incidence of cervicalcancer. In Japan, however, vaccination rates are still low
due to adverse side effects, and the incidence of cervicalcancer caused by HPV infection has not been controlled.
Histological type is one of the factors that affect the gradeof cervical cancer and the choice of treatment, but differential diagnosis is difficult because there is no diagnostic
marker for some subtypes of cervical cancers. In this project, we are analyzing gene expression profiles of cervicalcancer specimens by RNA sequencing in collaboration
with Hokkaido University Hospital and the Department of
Pathology, Hokkaido University Hospital (Figure 1), with

Fig. 1. Transcriptom analysis of HPV+ cervical cancers

the goal of making it possible to differentiate subtypes of43cervical cancers. We will continue to increase the number

hand, CagA, independent of its own phosphorylation,of specimens and conduct correlation analysis with clinicalbinds to the serine/threonine kinase PAR1b (also known

information.

as MARK2) and inhibits its kinase activity; since PAR1b(2) Analysis of the role of cytokine signals in COVID-19

plays an essential role in the formation and maintenanceprogression (Figure2)

of epithelial cell polarity, CagA-injected cells exhibit dis-

The Institute, led by the Center, was designated as arupted epithelial cell polarity. In addition, a recent study

sanitary laboratory for SARS-CoV-2 PCR testing in 2020,

found that PAR1b is essential for nuclear translocation ofand has established a system to conduct SARS-CoV-2 PCR

the tumor suppressor BRCA1 (Imai et al. Cell Host Microbe

testing from patient saliva in collaboration with the Hok-2021). Nuclear BRCA1 plays a protective role for DNA rep-

kaido University Hospital Laboratory. In addition, we arelication forks and is essential for homologous recombina-

also conducting research related to SARS-CoV-2. Publica-tion, a non-mutagenic DNA double-strand break repair

tion of a paper suggesting a relationship with cytokine sig-

pathway, and CagA inhibits BRCA1 nuclear translocation,nals (upper right figure). Studies are underway on type I

thereby destabilizing DNA replication forks and inducing

interferon signal analysis that suppresses viral infection

DNA double-strand breaks. Furthermore, the resulting(bottom right figure) and on IL-34, an inhibitory macro-DNA double-strand breaks were repaired by mutagenic

phage growth factor, and the mechanism of COVID-19

repair pathways other than homologous recombination,

exacerbation. In addition, in collaboration with the Hok-

leading to genomic instability. Thus, it is suggested that

kaido University Graduate School of Medicine, we con-

CagA induces genomic instability via PAR1b repression

ducted infection experiments using hamsters in the P3

and promotes cell tumorigenesis by enhancing cell prolif-

laboratory of the Animal facility and has published several

erative potential via SHP2 activation. Further studies will

papers.

be conducted to elucidate the full mechanism of cell tu-(3) Role of H. pylori in the development of gastric cancer

morigenesis by H. pylori CagA.

Chronic Helicobacter pylori (H. pylori) infection is associated with the development of gastric mucosal lesions such

The following equipment are installed in the Center.

as atrophic gastritis and gastric ulcer. Among them, cagA-1) C hemiluminescence and fluorescence imaging system

positive H. pylori carrying the cagA gene causes more severe gastric mucosal lesions than cagA-negative H. pylori,
and also significantly increases the risk of developing gastric cancer. Worldwide, cagA-positive strains account for
about 60% of all H. pylori isolates, but almost all H. pylori
collected from the stomachs of Japanese people are cagA-positive. The CagA protein produced by H. pylori is injected into human gastric epithelial cells by a needle-liketype IV secretion mechanism possessed by the bacteria.
Upon entry into the cells, CagA undergoes phosphorylation modification at specific tyrosine residues by host cellkinases. Tyrosine-phosphorylated CagA binds to the tyrosine phosphatase SHP2 and deregulates SHP2, resulting inaberrant activation of the Ras-Erk pathway. On the otherFig. 2. Possible molecular mechanism of severe COVID-19

Fig. 3. IVIS imaging system

44

for mice (IVIS imaging system IVIS Spectrum manufactured by Xenogen) (Figure3): This system is used for image analysis of trace amounts of light obtained fromchemiluminescence or fluorescence while mice and rats
are alive. The dark box for measurement is designed toblock even ultra small amounts of external light such ascosmic rays, and chemiluminescence/fluorescence is
detected using an ultra-sensitive cooled CCD camera.

Fig. 5. A whole body sagittal sections of mice2) X -ray CT imaging measurement system for mice (Latheta
LCT-200 Hitachi Aloka Medical, Ltd.): Imaging analysis ismately 8.3 s/300 mm in the general X-ray standard im-

performed by performing tomographic imaging while

aging mode. The maximum effective field of view is 300

keeping mice and rats alive. The standard scanning time

mm (in the direction of the body axis).

is approximately 10.6 s/rotation in the tomographic
standard imaging mode (360°acquisition) and approxi-3) T he Astrios is the world’s fastest automated cell separation and analysis system, capable of automatically analyzing and separating more than 30,000 cells per second. It is capable of high-speed separation and high cell
viability after preparative separation, making advanced
experiments possible.
4) M acrotome (Leica, CM3600XP) (Figure4): CM3600XP isa macrotome that can prepare frozen sections fromlarge specimens. It has been modified to optimize theuse of Kawamoto film developed by Dr. Tadafumi
Kawamoto of Tsurumi University. By using this macrotome, large frozen sections such as whole body sagittal
sections of mice (Figure5) and whole brains of macaque monkeys can be prepared in a very clean condition and used for subsequent immunohistochemistry
experiments. The ability to attach a tungsten blade andthe automatic feeding function enables stable preparation of thin sectioned specimens of hard tissues such as
bones and teeth.

Fig. 4. Macrotome

Teaching Staff

Professor

Masanori HATAKEYAMA, Ph.D.

Professor

Masaaki MURAKAMI, V.M.D., Ph.D.

Professor

Staff

Kohji MORIISHI,V.M.D., Ph.D.

PI, Professor

・
・
・
・
・
・
・
・
・
・
・
・ Masahiro SONOSHITA, Ph.D.

Professor

・
・
・
・
・
・
・
・
・
・
・
・ Masanori HATAKEYAMA, M.D., Ph.D.

Professor

・
・
・
・
・
・
・
・
・
・
・
・ Masaaki MURAKAMI, V.M.D., Ph.D.

Professor

・
・
・
・
・
・
・
・
・
・
・
・ Kohji MORIISHI, V.M.D., Ph.D.

Associate Professor ・・・・・・・・・・・・ Naoko KAMIYA, Ph.D.
Associate Professor ・・・・・・・・・・・・ Kumiko YOSHIMATSU, V.M.D., Ph.D.
Associate Professor

Naoko KAMIYA, Ph.D.

Associate Professor

Kumiko YOSHIMATSU, V.M.D., Ph.D.

Associate Professor

Associate Professor ・・・・・・・・・・・・ Hidemitsu KITAMURA, Ph.D.

Hidemitsu KITAMURA, Ph.D.

45

Education Activities
Academic staffs of Institute for Genetic Medicine, Hokkaido University are in charge of education for Graduate Schoolof Medicine, Graduate School of Science, Graduate School of Chemical Sciences and Engineering or Graduate Schoolof Life Science. Students can take Master Course and Doctor Course of Graduate School of Medicine, Doctor Course of
Graduate School of Science, Master Course and Doctor Course of Graduate School of Chemical Sciences and Engineering, and Master Course and Doctor Course of Graduate School of Life Science.

Division

Course Title
Master's Thesis Research in Medical Sciences Department of Stem Cell Biology

Division of Stem
Cell Biology

Basic Principles of Medicine Stem Cell Biology
Dissertation Research in Medical Sciences Department of Stem Cell Biology
Principles of Medicine Stem Cell Biology

Instructor
Toru KONDOH
Yuri SONNaoto OIKAWA

Biochemistry A (II)Division of Signalingin Cancer and Immunology

Modern Trends in Chemical Sciences and Engineering II
Akinori TAKAOKA

Introductory of Biological Chemistry
Natural and Applied Sciences Leading and Advanced Biological and Polymer Chemistry
and Engineering IIIA (Introduction to Basic Biological Chemistry)
Master's Thesis Research in Medical Sciences Department of Molecular Neuroimmunology

Division of Neuroimmunology

Basic Principles of Medicine Department of Molecular Neuroimmunology

Masaaki MURAKAMI

Dissertation Research in Medical Sciences Department of Molecular Neuroimmunology

Shintaro HOJYO

Principles of Medicine Molecular Neuroimmunology

Shigeru HASHIMOTO

Introduction to Basic Medicine
Master's Thesis Research in Medical Sciences Department of Cancer Biology
Division of Biomedical Oncology

Takako OSHIO

Dissertation Research in Medical Sciences Department of Biomedical Oncology

Ryodai YAMAMURA

Principles of Medicine Biomedical Oncology

Kohe ONUMA

Master's Thesis Research in Medical Sciences Department of Immunobiology
Division of Immunobiology

Basic Principles of Medicine Immunobiology
Dissertation Research in Medical Sciences Department of Immunobiology
Principles of Medicine Immunobiology

Division of Genome Biology

Masahiro SONOSHITA

Basic Principles of Medicine Biomedical Oncology

Pharmaceutical Science

Kenichiro SEINO
Haruka WADA
Nanumi HAN
Shinya OHTA

Biochemistry A (II)Division of Developmental Physiology

Introductory of Biological Chemistry
Natural and Applied Sciences Leading and Advanced Biological and Polymer Chemistry
and Engineering IIIA (Introduction to Basic Biological Chemistry)

Fumio MOTEGIModern Trends in Chemical Sciences and Engineering II
Division of Microbial Oncology

Pharmaceutical Science

Naoko KAMIYA

Master's Thesis Research in Medical Sciences Department of Functional Immunology
Division of Functional Immuonology

Basic Principles of Medicine Immunoregulation by Type 1/Type 2 Cytokines and Control of
Immune Diseases
Dissertation Research in Medical Sciences Department of Functional Immunology

Hidemitsu KITAMURA

Principles of Medicine Immunoregulation by Type 1/Type 2 Cytokines and Control of Immune Diseases
Higher Order Cellular Functions Lipid biology

Division of Molecular Interaction

Biosystems Science

Molecular Cell Biology

Pharmaceutical Science

Kazuma TANAKA

Natural and Applied Sciences Basic Biosystems Science

Takuma KISHIMOTO
Tomohiko OKAZAKI

46

Campus Map of Hokkaido University
Map of Sapporo Campus
Research and Education Center for Brain Science
Institute for Genetic Medicine
Central Institute of Isotope Science
Frontier Research in Applied Sciences Bldg.
Center for Language Learning
Center for Advanced Tourism Studies
The Open University of Japan;
Hokkaido Study Center
Health Care Center
Education and Research Center for
Mathematical and Data Science
Center for Natural Hazards Research

Asabu
Horse
Stables/
Track

American Footballand Lacrosse Field

Evacuation
AssemblyAreaute 452)

Ishiyama Street (Ro

（

（

）

TennisCourtsAthletics
Track
Evacuation
Assembly
Area）

BaseballField

Hockey/Handball
Field

）

｛
Kanjo
Gate

Kita 18-jo Street

North 18
Gate

Nishi 5-chome Street

North 15
Gate

Evacuation
Assembly
Area）
North 13
Gate

Kita 13-jo Street

SubwayKita 12-jo
Station(N)）

Subway Namboku Line

s

ru

(S)

s Court（ta

Evacuation
Assembly
Area

Tenni

O

SubwayKita 18-jo
StationInstitute for
Genetic Medicine

Soccer/
Rugby
Field

（

Gate

Headquartersof theHokkaido
Research
Organization

Elm Tunnel

Baseball
Field

Cafe

AED

North 20
Gate

Hokkaido
Hokkaido Sapporo
Technical High School Instituteof Public Hokkaido
HealthIndustrial
Research
Hokkaido Institute of
InstituteEnvironmental Sciences

Evacuation
Assembly
Area

Restaurant / Cafeteria

University Goods Shop（

Geological Surveyof Hokkaido

Information

Main
Gate

JR

South
Gate
H

Kita 8-jo Street

ak

od

at

eL

in

e

AED equipped facility

University Organization
Administration Bureau
Front Office for Human Resource Education and Development
Hokkaido University Hospital
Dental Clinical Division of Hokkaido University Hospital
Admission Center
Institute for the Advancement of Higher Education｛｛

Graduate Schools, Faculties and Schools
Graduate School of Humanities and Human Sciences
Graduate School of Law
Graduate School of Economics and Business
Graduate School of Education
Graduate School of International Media, Communication, andTourism Studies
Graduate School of Public Policy
Graduate School of Medicine
Graduate School of Biomedical Science and Engineering
Graduate School of Dental Medicine
Graduate School of Veterinary Medicine
Graduate School of Infectious Diseases
Graduate School of Health Sciences
Graduate School of Information Science and Technology
Graduate School of Environmental Science

Makomanai
Botanic Garden

JR Sapporo Station
Subway Sapporo Station

Graduate School of Science
Graduate School of Agriculture
Graduate School of Global Food Resources
Graduate School of Life Science
Graduate School of Engineering
Graduate School of Chemical Sciences and Engineering
Faculty of Pharmaceutical Sciences
Faculty of Advanced Life Science
Note: The Graduate School of Fisheries Sciences is located at
Hakodate Campus
Research Institutes & Centers
Center for Ainu & Indigenous Studies
Hokkaido University Press
Hokkaido University Archives
Slavic–Eurasian Research Center
Center for Experimental Research in Social Sciences
Information Initiative Center North/South Bldgs.
Archaeological Research Center
Center for Environmental and Health Sciences
Field Science Center for Northern Biosphere
Research Center for Integrated Quantum Electronics
Proton Beam Therapy Center47

Research Institutes/Centers (North Campus Area)
Creative Research Institution (CRIS)
Center for Innovation and Business Promotion,
Institute for the Promotion of Business-Regional
Collaboration
Hokkaido Collaboration Center
Center for Food & Medical Innovataion, Institutefor the Promotion of Business-Regional
Collaboration
Shionogi Innovation Center for Drug Discovery
Platform for Research on Biofunctional
Molecules (PRBM)
Frontier Research Center for Advanced Materialand Life Science
Arctic Research Center
Catalysis Research Center
Research Institute for Electronic Science
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Institute of Low Temperature Science
Veterinary Teaching Hospital
Facilities
Conference Hall
Clark Memorial Student Center
Career Center
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Furukawa Hall
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Building"Kodomo No Sono" Child Care Center
Faculty House Trillium
Experiment FarmStudent Services
Multimedia Education Building
Gym
Enyu Gakusha Community HallSports Training Center"Tomoni" Child Care Center
Student Communication Station
Libraries
Central Library
North Library
Dorms
Hokkaido University International House Kita 8(Kita 8 Nishi 11)
Keiteki-Ryo Student Dormitory(Kita 18 Nishi 13)
Hokkaido University International House Kita 23(Kita 23 Nishi 13)
Foreign Scholars' Accommodation(Kita 24 Nishi 12)
Tourist Spots
Sakushukotoni River
Central Lawn
Bust of Dr. William S. Clark
Elm Grove
Former School of Agriculture Library
The Hokkaido University Museum
Monument to First Artificial Snow Crystal
Ono Pond
Monument in Honor of Dr. Inazo Nitobe
Flowering Tree Garden
Poplar Avenue
Gingko Avenue
Heisei Poplar Avenue
Site of Old Village
The Second Farm (Model Barn)
Botanic Garden
Cafeterias/Restaurants/Stores
Information Center "Elm Forest Shop"
Hokkaido University (HU) Co-op
Clark Cafeteria
Chuo Cafeteria, HU Co-op
Restaurant Elm
Restaurant Royal
Hokubu Cafeteria, HU Co-op
Restaurant Poplar
Hokudai Marche Café and Labo
Seicomart

Information Center "Elm Forest Shop"

The University Information Center is locatedjust inside the main gates of Sapporo Campus.
Visitors can browse information regarding
campus events as well as enjoy refreshmentson the outdoor patio. The Center also carries
original Hokkaido University merchandise.

Opening hours:
8:30–17:00
Closed:December 29–January 3

Institute for Genetic Medicine,
Hokaido University 2022
2022--2023
February 2023

N15 W7, Kita-ku, Sapporo 060-0815 Japan TEL(011)716-2111 FAX(011)717-5286
URL：https://www.igm.hokudai.ac.jp/

HOKKAIDO UNIVERSITY
Institute for Genetic Medicine 2022-2023

Institute for Genetic Medicine, Hokkaido University