Research & Educational|Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, The University of Tokyo

Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, The University of Tokyo
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Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, The University of Tokyo

Department of Pharmacy

Dean Hiroyuki Arai
(2017.5.16Updated)
*:Medicine science department chair
*:Pharmacy department chair

Laboratory of Chemistry and Biology

http://www.f.u-tokyo.ac.jp/~taisha/en/
Prof. Y. Urano
Assoc. Prof. K. Hanaoka
Assist. Prof. T. Ueno

We create a novel research field termed "Chemical Biology" so as to promote development of life sciences and medicine.

Research Topics
  1. Development and application of functional contrast agents of magnetic resonance imaging (MRI)
  2. Theoretical design and development of fluorescent probes for living cells, and their in vivo application for clinical use
  3. Rational design and development of novel fluorophores and their application for fluorescent probes
  4. Research on drug discovery: Development of chemical compounds that control disease-related proteins, and development of high-quality screening systems

Our laboratory conducts research on the analysis and modification of dynamic living systems, using chemistry as a powerful tool. In particular, we address two research themes: bioimaging and drug discovery. With respect to the first topic, one of the important goals in modern life sciences is to elucidate the dynamic behaviors of biomolecules in situ in the living cells/organisms. Because spatiotemporal information of molecules is lost once the cells/tissues are homogenized for subsequent analysis, it is important to develop functional bioimaging probes that can be used in the systems. So far, our laboratory has developed bioimaging probes based on the design strategies we established by ourselves. The other goal of our group is to achieve university-driven drug discovery using a chemical library containing over 200,000 compounds, with our original screening systems. We are searching for novel lead compounds to cure diseases that are too challenging to address for private companies. The above-described two areas of research have attracted enormous attention in recent years under the name of "Chemical Biology", and we believe that they will open up new horizons in life sciences.

Laboratory of Protein Structural Biology

http://www.f.u-tokyo.ac.jp/~kouzou/index_e.html
Prof. T. Shimizu
Assoc. Prof. U. Ohto
Assist. Prof. S. Toma

Determining three-dimensional structures of proteins and nucleic acids, and elucidating their functions in living cells

Research Topics
  1. Structural biology of proteins and nucleic acids using X-ray crystallography and small angle X-ray scattering
  2. Structure and function relationship of proteins and nucleic acids
  3. Structures of nuclear proteins and their complexes
  4. Structures of proteins in homologous recombination
  5. Structures of immune-system and membrane proteins, and their complexes

Structural biology elucidates three-dimensional structures of proteins and nucleic acids and also biological phenomena such as their activities, functions, properties, interactions, and roles in living cells. In the elucidation of three-dimensional structures, X-ray crystallography is extensively used since this method provides us with detailed structural information on the biological functions and roles. We also take an interdisciplinary approach, combining methods of biophysics, biochemistry, molecular biology, genetic and protein engineering, and small angle X-ray scattering. With this structural biological approach, we can obtain the information on three dimensional structures that are required for drug design and discovery.
Based on this foundation of the research and the objectives, we carry out structural biological researches into nuclear proteins, proteins in homologous recombination and immune-system proteins.
Three dimensional structure of nuclear protein, nucleomethylin
Three dimensional structure of nuclear protein, nucleomethylin 
Three dimensional structure of immune-system protein, MD-2 in complex with lipid
Three dimensional structure of immune-system protein, MD-2 in complex with lipid 

Laboratory of Immunology and Microbiology

http://www.f.u-tokyo.ac.jp/~bisei/
Prof. S. Hori
Assoc. Prof. C. Kaito
Assist. Prof. A. Nakajima
Assist. Prof. R. Murakami

Understanding the principles of immunological tolerance and homeostasis

Research Topics
  1. Mechanisms of immunological tolerance and homeostasis
  2. Mechanisms of regulatory T cell development and function
  3. Molecular mechanism of bacterial virulence
The immune system has evolved the ability to distinguish "self" from "non-self" to maintain homeostasis of the body. The immunological "self" is established in an adaptive and acquired manner through continuous interactions with changing internal as well as external environments. The ultimate goal of this laboratory is to elucidate, throughout multiple layers, from molecules, cells, cell populations, tissues, to individuals, the principles that govern the development of such immunological "self" and its transformation during diseases. Towards this end, we focus on a cell-extrinsic, dominant control mechanism of the immune system that depends on a subpopulation of T lymphocytes called regulatory T (Treg) cells. As one approach, we elucidate how mutations in the Foxp3 gene, encoding a transcription factor critical for Treg cell development and function, lead to a breakdown of immunological tolerance and homeostasis.
Disintegration of immunological “self” underlies a variety of diseases
Disintegration of immunological “self” underlies a variety of diseases 
Foxp3-expressing regulatory T (Treg) cells are indispensable for immunological tolerance and homeostasis
Foxp3-expressing regulatory T (Treg) cells are indispensable for immunological tolerance and homeostasis 

Laboratory of Bioorganic Chemistry (Institute of Molecular and Cellular Biosciences)

http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html
Prof. Y. Hashimoto
Assoc. Prof. M. Ishikawa
Lecturer S. Fujii

Discovery and production of bioresponse modifiers directed toward an understanding of life phenomena

Research Topics
  1. Discovery and production of molecules that control the spatio-temporally dependent expression and function of proteins
  2. Medicinal chemistry of nuclear receptor ligands
  3. Design and synthesis of bioresponse modifiers that control the topology and dynamism of proteins
  4. Developing new methods of drug discovery, using the multifunctional thalidomide as a template

The aims of this laboratory are to discover and produce new bioresponse modifiers based on medicinal and synthetic organic chemistry, and to use them to gain an understanding of life phenomena.
Many life phenomena are controlled by the expression, localization, and degradation of proteins. Thus far, research on chemical control of the expression of proteins has succeeded in discovering and producing various nuclear receptor ligands.
At the same time, functional molecules that regulate life phenomena through modification of proteolysis have been designed and produced. By a method differing from siRNA, it has become possible to destroy target proteins at any time, and this is expected to serve as a new technique for the functional analysis of proteins within cells.
In addition, we are designing and synthesizing molecules that control the folding process of proteins. These are compounds that control dynamic structure‒based function of proteins, and they will open up new domains in medicinal chemistry of bioresponse modifiers. We are also producing bioresponse modifiers using multifunctional thalidomide as a drug discovery template.
One research project on the  control of protein structure and folding by low-molecular weight compounds  is addressing the  correction of intracellular localization anomalies in rhodopsin with a mutation resulting in misfolding.  In this example, the focal point is placed on retinitis pigmentosa caused by a rhodopsin mutation, but in the future, we plan to apply these methods broadly to a variety of diseases based on misfolding in specific proteins.
One research project on the control of protein structure and folding by low-molecular weight compounds is addressing the correction of intracellular localization anomalies in rhodopsin with a mutation resulting in misfolding. In this example, the focal point is placed on retinitis pigmentosa caused by a rhodopsin mutation, but in the future, we plan to apply these methods broadly to a variety of diseases based on misfolding in specific proteins. 

 
This is an example of research on the discovery and production of target proteolysis inducers. We used the ubiquitin ligase activity of cIAP1 to design and produce various kinds of molecules that induce the ubiquitination of target proteins and their degradation by proteasomes.
This is an example of research on the discovery and production of target proteolysis inducers. We used the ubiquitin ligase activity of cIAP1 to design and produce various kinds of molecules that induce the ubiquitination of target proteins and their degradation by proteasomes. 

Laboratory of Molecular Pharmacokinetics

http://www.f.u-tokyo.ac.jp/~molpk/en/index.html
Prof. H. Kusuhara
Lecturer K. Maeda
Assist. Prof. H. Hayashi
Assist. Prof. T. Mizuno

Elucidation of the mechanisms determining pharmacokinetic properties of drugs that contributes to drug design, and safe and effective utilization of drugs

Research Topics
  1. Prediction of pharmacokinetic properties and responses of drugs based on in vitro experiments: analysis of the effect of genetic polymorphisms and drug-drug interactions
  2. Elucidation of transporters determining the elimination pathway of drugs, and drug transport systems at the blood-brain barrier
  3. Elucidation of mechanisms for the membrane trafficking of transporters
  4. Development of transporter-based drug delivery systems (DDS)
  5. Elucidation of mechanisms of drug-induced toxicity
  6. Elucidation of genetic and epigenetic regulation of drug transporters

Pharmacological and adverse effects of drugs depend on their pharmacokinetic properties, which determine their exposure to the targets. Our laboratory aims to establish methods for quantitative and theoretical prediction of pharmacokinetic properties of new chemical entities in humans based on the molecular mechanisms. In particular, we investigate the impact of transporters on the elimination of drugs from the liver and kidney, the distribution of drugs into their target organs e.g., the brain, and drug absorption in the small intestine, in order to develop drug screening systems and to elucidate the mechanisms of drug-drug interaction, and interindividual variation in pharmacokinetics of drugs. We have also started research on the regulation of membrane trafficking of the transporters using low molecular weight compounds to cure transporter related-diseases. Research achievements in this laboratory contribute to predicting and evaluating rational pharmacokinetic properties in drug development, drug review and regulation, and in clinical use, and to developing medical therapy for transporter related-diseases.
An example of a drug successfully designed to minimize interindividual variation in pharmacokinetics by considering transporter characteristics.
An example of a drug successfully designed to minimize interindividual variation in pharmacokinetics by considering transporter characteristics. 
As a high-throughput screening system for hepatobiliary transport, uptake and efflux transporters are simultaneously expressed in a single polarized cell (double transfectant).
As a high-throughput screening system for hepatobiliary transport, uptake and efflux transporters are simultaneously expressed in a single polarized cell (double transfectant). 

Laboratory of Chemical Pharmacology

http://www.yakusaku.jp/home_e.htm
Prof. Y. Ikegaya・Y. Sekino
Assoc. Prof. R. Koyama
Assist. Prof. T. Sasaki
Assist. Prof. A. Nakashima

Pharmacological approach toward the brain: from molecule to animal

Research Topics
  1. Study on neuronal networks involved in learning and emotion using neuronal activity genetic markers
  2. Study on brain network operation using functional imaging of multicellular activity
  3. Studying on neuronal network formation during development

Pharmacology includes two aspects: 1) to analyze the biological action of drugs and 2) to search the strategies for developing treatments for diseases. We conduct our pharmacological research by taking advantage of state-of-the-art technologies and a wide range of knowledge from molecule to animal.
We focus on the roles of the cerebral limbic system and cerebral cortex, in particular, the hippocampus and amygdala, which are involved in learning, memory, and emotion.
Our experimental techniques cover from genetics, biochemistry, and cell biology to electrophysiology, histochemistry, and behavioral pharmacology. Recent technical advances have allowed us to investigate the neuronal network dynamics on far larger scales than hitherto. Functional multineuron calcium imaging reveals the dynamics of network activity with single cell/synapse resolution (Upper Figure), through which we elucidate the structural and functional relationship that generates spatiotemporally organized spike patterns. We also address the mechanisms of learning and memory using in situ mapping learning-relevant neuronal circuits with immediate early genes with cellular and temporal resolution (Lower Figure). We believe that these novel approaches open up a new avenue for our mesoscopic understandings of network function and malfunction associated with depression, stress-relevant disease, and epilepsy.

Laboratory of Neuropathology and Neuroscience

http://www.f.u-tokyo.ac.jp/~neuropsc/
Prof. T. Tomita
Assist. Prof. Y. Hori
Assist. Prof. S. Takatori
Assist. Prof. G. Itoh

From understanding the molecular pathogenesis of neurodegerative and psychiatric diseases to development of therapeutics and novel basic science

Research Topics
  1. Understanding the molecular mechanisms of intramembrane proteolysis by γ-secretase
  2. Research on Aβ metabolism (production, secretion and clearance) and its regulatory mechanisms
  3. Elucidation of pathophysiological functions of risk factors for Alzheimer diseases
  4. Molecular mechanisms of aberrant vesicular trafficking and diseases
  5. Biological and pathological roles of synaptic adhesion molecule and its metabolism
  6. Understanding the cellular pathology of glial cells towards development of glia-targeting drugs
  7. Elucidation of the molecular pathomechanisms of Parkinson disease

Aim of our laboratory is that understanding the molecular pathogenesis of neurodegenerative and psychiatric diseases to develop novel approaches to therapeutic, prevention and diagnosis. Also, we are pursuing novel basic science by understanding the molecular basis of diseases. Especially, we are studying Alzheimer disease, autism spectrum disorder and schizophrenia to identify the pathological mechanisms and therapeutic targets of these diseases at molecular levels. To understand the disease condition, we have to realize the basic mechanisms of cells and living organisms, and vice versa. We believe that this disorder-to-normal cycle in research is a basis of modern disease and basic biology, and bolsters both scientific areas by novel knowledge and technology. From this standpoint, we proceed disease-oriented molecular and cellular research in a multidisciplinary manner by mutual collaborations with organic chemists, structural biologists, physicians and pharmaceutical companies.
 
Aβ metabolism in the pathogenesis of Alzheimer disease
Aβ metabolism in the pathogenesis of Alzheimer disease 
Pathological analysis of genetic protective factor for Alzheimer disease in vivo
Pathological analysis of genetic protective factor for Alzheimer disease in vivo 

Laboratory of Clinical Pharmacokinetics (The University of Tokyo Hospital)

http://plaza.umin.ac.jp/~todaiyak/en_index.php
Prof. H. Suzuki
Lecturer T. Takada
Lecturer M. Honma

Systems-pharmacological studies for drug development in the next-generation

Research Topics
  1. Therapies for lifestyle-related diseases based on the comprehensive understanding of molecular mechanisms that control the transport of endogenous small molecules
  2. Therapies for bone metabolism diseases based on the comprehensive understanding of the dynamic control mechanisms of signal molecules involved in bone resorption and formation
  3. Quantitative understanding of the pharmacological and toxicological effects of molecular targeted anti-cancer drugs to establish clinical applications and new drug discovery techniques
  4. Large-scale omics analysis to establish methods of preventing and treating adverse drug reactions based on the quantitative understanding of underlying molecular mechanisms
  5. Clinical pharmacokinetics based on detailed quantification of related molecular functions

It has been recognized very well that we need to describe / predict the functions of cells, tissues and organisms from the function of each constituent molecule in a quantitative manner in order to understand the life activities. Although we have used such approach in analyzing and predicting the drug disposition in humans, it is quite important for us to expand the concept to the analysis of pharmacological / toxicological actions of drugs in humans. We are using such "systems-pharmacological" methods to solve many kinds of problems that remain great challenges in drug discovery, such as how to identify the most effective target molecules among numerous candidates, and how to comprehensively predict the adverse drug reactions in humans.

 

 

Endowed Laboratory of Drug Lifetime Management

http://www.f.u-tokyo.ac.jp/~druginfo/index.html
Visiting Prof. Y. Sawada
Assoc. Prof. S. Hori・ H.Satoh
Lecturer A. Miki
Assist. Prof. H. Tamaki

Drug lifetime management

Research Topics
  1. Development and practice of methodologies for the collection, evaluation, analysis, and distribution of drug information
  2. Specification, standardization, and digitization of drug information, and their applications
  3. Quantitative prediction of the effects of biodisturbance factors on pharmacokinetics and drug effects
  4. Quantitative analysis of transplacental transfer of drugs and prediction of fetal toxicity

Our university’s Faculty of Pharmaceutical Sciences bears the social mission of promoting drug discovery and the proper use and evolution of drugs while improving the quality of drug therapies. To these ends, this course in Drug Informatics pursues various research to ensure that the developed drugs can amply exhibit their effects and lead a substantial "drug life." This is what we call "drug lifetime management."
The research topics of this course are that (1) the proper collection of drug information (DI), (2) evaluation/analysis based in pharmacokinetics and pharmacodynamics, (3) quantitative prediction of changes in pharmacokinetics and drug effect due to various risk factors, (4) optimal specification/standardization/digitization, and (5) the proper provision of DI to the actual scene of medical treatment. Concretely speaking, the content of our research is broad-ranging, extending from the creating new DI through in vitro experiments and clinical studies, to the construction of computer systems that support drug therapy, and research on development of systems for analyzing, sharing, and utilizing various kinds of DI (including events related with drug therapies) from the clinical field.
The central dogma of pharmaceutical development consists of the cycle of drug discovery -- proper use of drugs -- post-marketing drug development -- drug discovery and so on
The central dogma of pharmaceutical development consists of the cycle of drug discovery -- proper use of drugs -- post-marketing drug development -- drug discovery and so on 
Pattern diagram of experimental method using human placental perfusion to study the degree to which drugs pass into the fetus from the mother
Pattern diagram of experimental method using human placental perfusion to study the degree to which drugs pass into the fetus from the mother 

Laboratory of Pharmaceutical Regulatory Science

http://www.f.u-tokyo.ac.jp/~regsci/eindex.html
Visiting Prof. Y. Fujiwara
Assoc. Prof. S. Ono
Lecturer T. Yamamoto

Establishing scientific drug evaluation

Research Topics
  1. Economic and regulatory impact on global pharmaceutical R&D activities
  2. Regulatory review and approval of new drugs
  3. Roles of 'ethnic differences' in decisions of drug development
  4. Drug safety and regulatory environments

The goal of our research is to establish scientific principles and methods in drug evaluation with societal perspectives in mind. Pharmaceutical research and development (R&D), clinical development in particular, regulatory review and approval of new drugs, and post marketing activities are our research interests. We provide evidence on R&D efficiency, performance and outcomes of regulations, and public health impact through rigorous analysis based on economic models. Conflicts in global pharmaceutical R&D, including recent launch delay of new drugs in Japan and so-called ethnic differences, are always high on our agenda. Aside from the research activities, we also make efforts to develop human resources in both private and public sectors with up-to-date knowledge, ethics, and philosophy, and rationale in drug evaluation. We offer lectures for graduate and undergraduate students, and a half-year training course for industry and regulatory professionals. We aim to secure transparency and social responsibility on drug regulation through our research and educational programs.

Endowed Laboratory of Drug Policy and Management

http://www.f.u-tokyo.ac.jp/~utdpm/
Visiting Prof. K. Tsutani
Assoc. Prof. A. Igarashi

With the goal of rational use of medical resources, we open up a new domain of scholarship merging natural and social sciences

Research Topics
  1. Generic drugs and policy development for their rational use
  2. Pharmacoeconomic analysis of expensive drugs, like biologics
  3. Individualized treatment through pharmacogenetics
  4. Analysis of the present status of complementary and alternative medicine (CAM), and research into its safety, efficacy, and economy
  5. Elimination of the pharmaceutical gap

Medical expenses are growing by the year, and present health-insurance system is at a crossroads. In order to utilize pharmaceuticals appropriately within a limited budget (what we call the "rational use of pharmaceuticals"), we have to evaluate efficiencies of various drugs. When we evaluate efficiency, we need to measure both clinical evidence, which endpoints are efficacy and safety, and economic evidence, of which the primary index is economy. In this course, we carry out economic evaluations of drugs that are either under development or already marketed (drugs for rheumatoid arthritis, cancer, smoking cessation therapy, hypertension, etc.)
It is important for us to set various perspectives, including regulatory administration, corporations, medical institutions, and patients, when we take economic evaluations. In this course, from societal perspective that includes all of above-mentioned perspectives, we explore the appropriate role of pharmaceuticals in health services.
After researching methodologies for evaluating them, conducting actual analyses, and analyzing policy, etc., we endeavor to recycle our findings back into society through policy proposals and the like.

 
Linked site providing a source of foreign drug price data:Global atlas of drug prices  URL: http://dprice.umin.jp/
Linked site providing a source of foreign drug price data:Global atlas of drug prices URL: http://dprice.umin.jp/ 

Endowed Laboratory of Pharmaco-Business Innovation

http://www.f.u-tokyo.ac.jp/~pbi/english/index.html
Visiting Prof. H. Kimura
Prof. K. Imamura
Assoc. Prof. E. Shimizu

Developing a professional who Understand Both Life Sciences and Business

Research Topics
  1. Studies on industry dynamics in pharmaceutical/life science domain: Analysis of factors driving the reorganization of the industry
  2. Studies on strategy and management issues in pharmaceutical/life science domain: Finding solutions for management issues of companies, universities, and medical institutions
  3. Studies on industrial policy in pharmaceutical/life science domain: Making recommendations on social infrastructure for the development of the industry

While Japan aims at sustainable development for the future as a world leader in science and technology, pharmaceutical/life science domain occupies an important position in the national strategy. On the other hand, in a globalizing pharmaceutical industry, the presence of Japan as a market has relatively been declining little by little.
Under such circumstances, the objective of PBI course is to contribute to a sustainable development of the Japanese pharmaceutical industry by 1) conducting multilateral research on managerial issues of rapidly evolving pharmaceutical/life science industry for its long-term growth, such as those related to innovation, public health, global competition and harmonization, 2) fostering a new generation of industrial leaders capable of taking advantages of the new opportunities that are being created, and 3) developing a social infrastructure for drug discoveries including regulations.
Figure: Basic concept of PBI
Figure: Basic concept of PBI 
A lecture from the PBI Seminar
A lecture from the PBI Seminar 


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