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Masanari Itokawa / Professor / Division of Clinical Medicine & Sciences
Department of Computational Biology & Sciences / / Molecular Biology of Psychiatric Illnesses
http://www.igakuken.or.jp/schizo-dep/

Career Summary
Education:
1989 M.D. magna cum laude, Saitama Medical School
1996 Ph.D. Tokyo Medical and Dental University/ School of Medicine

Professional Training, Employment, and Fellowships:
1989 Passed the Examination of National Board
1989-1990 Resident in Department of Neuropsychiatry, Tokyo Medical and Dental University/ School of Medicine, Tokyo
1990-1991 Psychiatrist at Yotsukura Hospital, Fukushima
1991-1993 Research Fellow in Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki
1993-1994 Research Associate and Psychiatrist in Department of Neuropsychiatry, Tokyo Medical and Dental University/ School of Medicine, Tokyo
1994 Designated Physician of Mental Health licensed by The Ministry of Health and Welfare
1994-1996 Research Associate in Department of Biochemistry, Institute for Brain Research, Faculty of Medicine, University of Tokyo, Tokyo
1996-1997 Research Associate in Department of Neuropsychiatry, Tokyo Medical and Dental University/ School of Medicine, Tokyo Psychiatrist in Takatsuki Hospital, Tokyo
1997-1999 Visiting Fellow in Molecular Neurobiology Branch, National Institute on Drug Abuse, National Institute of Health, Baltimore, MD, USA
1999-2001 Researcher in Lab. for Molecular Psychiatry, BSI, RIKEN, Saitama
2001-2011 Project Leader, Schizophrenia Research Project, Tokyo Institute of Psychiatry, Tokyo
2011-2015 Project Leader, Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo
2015-present Director, Center for Medical Cooperation, Tokyo Metropolitan Institute of Medical Science, Tokyo

Educational Activities
Professor, Tokyo Medical & Dental University
Assistant Professor, Saitama Medical School

Research Activities
Why do homo sapiens suffer from mental illnesses? Numerous people in the fields of religion and philosophy have investigated this maze from far in the past. However, the medical sciences have only been involved in this issue for the last 300 years. We are challenging ourselves to resolve the twister interwoven with brain and mind by using the methods and tools of biology.
Functional psychiatric disease is a brain disorder causing emotional and thinking difficulties without any abnormal signs showing up in electric encephalography or brain imaging. Schizophrenia is the major one of these, along with mood disorders.
We perform genomic and metabolome analysis using blood samples from patients with schizophrenia in order to investigate the pathophysiology of the disease. We create animal and culture cell-based models utilizing genetic polymorphisms and aberrant metabolism seen in the patients.
Human iPS cells induced from a schizophrenic patient carrying the rare genetic variation were differentiated to neural cells to be analyzed in this investigation.
Schizophrenia is a relatively common disease, with a prevalence of around 1% of the population of any given region in the world. Why has schizophrenia survived natural selection during human evolution? We are also seeking to answer this question by using our animal and culture cell models.
Ego function such as self-identity is also disturbed in patients with schizophrenia. We are attempting to reveal ego and self-consciousness, areas that up to now have been investigated primarily by those in the religion or philosophy fields, by using the tools and methods of molecular biology.
Oxidative stress is a central mediator of advanced glycation end product (AGE) formation, and pyridoxamine [vitamin (vit)B6]] (biosynthesized from pyridoxal in vivo) is known to detoxify reactive carbonyl compounds (RCOs) via carbonyl-amine chemistry. Cellular removal of AGEs hinges largely upon the activity of the zinc metalloenzyme glyoxalase I (GLO1). We detected idiopathic carbonyl stress in a subpopulation of schizophrenia. We first found an interesting case carrying a genetic defect of glyoxalase 1 (GLO1) that increased AGEs and decreased vitamin B6, since GLO1 detoxifies AGEs and vitamin B6 is a carbonyl scavenger. We discovered that 20% of patients showed signs of carbonyl stress by expanding our concept to cover general schizophrenic patients. In this way, we can resolve the problem of research on schizophrenia derived from the heterogeneity of the disease. The genetic defect of GLO1 contributes to the stress in the form of a five times higher risk compared to that of an intact gene. We found that AGEs level was significantly correlated with negative symptoms of the patients. Pyridoxamine, active vitamin B6, could be the first medicine suitable for treating the negative symptoms of schizophrenia, as most of the antipsychotic medicines in use today are not effective for negative symptoms.



Literature
Nishizawa D. et al. Mol Psychiatry 19(1):55-62, 2014
Ichikawa T. et al. Mol Genet Metab 105(1):103-109, 2012
Arai M. et al. Arch Gene Psychiatry 67:589-597, 2010
Doi N. et al. PLoS One 4(11):e7799, 2009
Hiroi N. et al. Proc Natl Acad Sci U S A. 102:19132-19137, 2005
Sora I. et .al. Proc Natl Acad Sci U S A. 98:5300-5305, 2001
Lin Z. et al. FASEB J. 14(5):715-528, 2000

Other Activities
Director, Japan Schizophrenia Research Society
Councilor, Japan Biological Psychiatry
Councilor, Japanese Society of Neuropsychopharmacology

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Future Plan
The brain is the last research field in the life sciences that remains unclear. Although individual elements of psychological and psychiatric phenomenon such as memory, learning, perception, and decision-making have been well analyzed and made clear, thus far the tools of brain science have been unable to provide adequate insight on higher brain functions such as self-awareness, independence, and ego. Our objective is to solve the mysteries of these mental phenomena by using molecular biology as a major tool along with the tools available to us in the philosophical and life sciences in order to clarify the higher brain functions.


Messages to Students
Research can be thought of as the attempt to see things that have never been seen before. We can experience the delight of discovery and the end of steady, lonely effort, like creating a road in the wilderness. We look forward to seeing motivated students.

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