Research/The University of Tokyo

Laboratory of Organic and Medicinal Chemistry

https://yakka.f.u-tokyo.ac.jp/english/index.html
Assoc. Prof. : Y. Otani

Synthesis of novel intelligent molecules which link chemical structures to biological functions in organic and medicinal chemistry 

Research Topics

1. Synthesis of new compounds exhibiting characteristic structural features and properties, finally relevant to biological functions
2. New reactions to functionalize aromatic compounds based on designed superelectrophiles
3. Design and synthesis of intelligent molecules, which will have impacts on functions of membrane proteins
4. Computational modeling and simulations of organic and macromolecular systems

Our aims of researches emphasize on design and synthesis of structurally novel organic molecules, which are characteristic in terms of structural (bonding) features and intrinsic functions such as chemical reactivities and biological functions. Designs of such novel molecules are based on our finding new chemistry including groundstate stable non-planar amide peptides and nitrosamines, and structures of multiply positively charged molecules. We study nitrogen-pyramidal amides and related nitrosamines, i.e., molecules that take nonplanar structures, different from the common planar amides. We apply this chemistry to construction of molecules of highly ordered structures such as helix peptide mimetics stable in water. We also develop new chemistry involving dication or trication molecules and apply them as superelectrophiles to synthesize a variety of novel multifunctionalized aromatic compounds, which are pharmaceutically relevant. We are also creating chemical molecules, which will be useful to controlling biological events of membrane proteins such as ion channels, neurotransporters and G-protein-coupled receptors. These molecules also contribute to understanding the physiological functions of these membrane proteins. We combine all the experimental projects with computational chemistry, which will lead to deep understanding of the underlying chemistry.

Helical structure of artificial amino acid peptide stable in water

Chemical modulation of functions of membrane proteins

Laboratory of Synthetic Natural Products Chemistry

https://inoue.f.u-tokyo.ac.jp
Prof. : M. Inoue
Assoc. Prof. : H. Itoh
Assist. Prof. : K. Hagiwara
Project Assist. Prof. : H. Fujino

Total synthesis and functional analysis of biologically active natural products

Research Topics

1. Development of new synthetic methodologies for total synthesis
2. Total synthesis of highly oxygenated polycyclic natural products
3. Total synthesis and functional analysis of ion channel-forming molecules
4. Total synthesis and functional analysis of antimicrobial molecules
5. Synthesis of new artificial molecules by modification of natural products templates

Natural products have been tremendously important in biology and human medicine because of their power to modulate signal transductions of biological system. Since the removal of sub-structures of the natural products often leads to significant losses of their activity, total chemical syntheses of their entire structures with a precision at an atomic level are necessary to provide sufficient amounts of material required for biological and medical applications. Architecturally complex natural products with molecular weight over 1000 are capable of highly specific interactions with their target proteins. Therefore, they are powerful agents for selectively controlling intricate biological systems. The goal of our research program is efficient, practical and flexible syntheses of gigantic natural molecules, which include highly oxygenated polycyclic natural products as well as ion channel-forming peptides. At the core of this research program is the development of new strategies for assembling architecturally complex natural products in a concise fashion. These synthetic developments would enable unified synthesis of new artificial analogs by modification of natural products templates. The new synthetic methods for the natural products and the synthetic analogs will allow us to tailor and enhance their drug like properties, to gain control over diverse signal transductions thereby offering new research methods for the study of life science.

Total synthesis of highly oxygenated polycyclic natural products

Total synthesis and functional analysis of biologically active peptides

Laboratory of Synthetic Organic Chemistry

https://gousei.f.u-tokyo.ac.jp
Prof. : M. Kanai
Assoc. Prof. : S. Kawashima
Assist. Prof. : H.Mitsunuma
Assist. Prof. : Y.Yamanashi
Project Assist. Prof. : M.Yamane

Catalysis for clean, robust, and concise complex molecule synthesis and new modal medicine

Research Topics

1. Development of new catalysis to facilitate complex molecule synthesis
2. Clean, robust, and concise synthesis of pharmaceuticals and their leads
3. Catalytic H₂ and O₂ activation
4. Conceptually new approach to promote human health

The main theme of our research is the development of revolutionary catalyses facilitating new drug design and synthesis. In this direction, we would like to promote human health based on the catalysis development. Chemical synthesis in 21st century should be clean, robust, and concise, no matter how complex the target molecules are. The "ideal synthesis" will be only possible by new catalytic methodologies. Moreover, new catalyses will expand the diversity of readily available building blocks, leading to structurally novel artificial drug design. Sustainability based on new catalysis is another direction of our research. Specifically, we are interested in catalytic activations of small molecules such as H₂ and O₂.

New Catalysis and Drug Lead Discovery/Optimization

Respiratory C-C Bond-Forming Catalysis

Iterative Polyol Synthesis

Laboratory of Natural Products Chemistry

https://tennen.f.u-tokyo.ac.jp/head.htm
Prof. : I. Abe
Assoc. Prof. : T. Mori
Assist. Prof. : T. Mizutani

We establish the mechanisms of natural product biosynthesis as a science in their own right, to construct a rational system for the production of new and useful substances

Research Topics

1. The biosynthesis and bioengineering of medicinal natural products
   (genome mining, engineered biosynthesis)
2. The enzyme biocatalysts (structure-function analysis, enzyme engineering, mechanistic studies)
3. The search for bioactive substances and isolation/structure determination

Natural organic compounds, prominent among which are antibiotics such as penicillin, are gifts from nature, and the benefits they have bestowed upon humankind as sources for the pharmaceuticals, etc., that maintain health is inestimable. In our laboratory, we study the process of biosynthesis of natural organic compounds produced by plants and microorganisms, using not only the foundation discipline of organic chemistry, but also incorporating the methods of biochemistry and molecular biology in an effort to understand the enzymes that catalyze each biosynthesis reaction and the functions and control mechanisms of the genes that govern their expression at the molecular level. In addition, we are expanding our research into "biosynthesis engineering," by which rational systems for the biological production of new and useful substances can be designed and constructed, based on the mechanisms of biosynthesis that have been brought to light. We also are carrying out research on the mechanisms by which the bioactivity of natural products is expressed, while at the same time searching for natural products that are active in intracellular signaling.

 

Concept of biosynthesis engineering, by which non-natural compounds are generated

Plant polyketide based on crystalline structure function control of synthetic enzymes and the production of substances

Laboratory of Advanced Elements Chemistry

https://kisoyuki.f.u-tokyo.ac.jp
Prof. : M. Uchiyama^◎
Project Assoc. Prof. : M. Nakajima
Lecturer.：N. Toriumi
Assist. Prof.：Y. Nagashima

 

Understanding of chemical phenomena at the atomic and electron levels and creation of a new science of materials through flexible construction of molecules

Research Topics

1. Development of advanced molecular transformation methods supporting materials science and life sciences (methodology development/synthetic chemistry)
2. Periodic table-traversing chemistry that transcends the frameworks of organic chemistry, inorganic chemistry, and metallic chemistry (elements chemistry)
3. Elucidation of the structural chemistry of intermediates and transitional states (physical chemistry, spectroscopy, theoretical calculation)
4. Design and production of materials founded on synthetic chemistry, spectroscopy, and computational chemistry (materials science/life sciences)

Our laboratory focuses on understanding the properties and phenomena of substances by "language of chemistry" such as molecules, atoms, and electrons (Seeing /Knowing); on developing reactions that manipulate the bonds between atoms completely in control (Designing); and on producing functional materials (Producing).
In our laboratory, we strive to develop technologies for the precise chemical conversion of tiny, tiny molecules less than 1 billionth of a meter in size (nanometer scale; nm). Thanks to recent advances in spectroscopy and theoretical calculation, it is getting possible to accurately predict and reproduce snapshots of the state of the electrons that form materials, as well as of reactions between molecules. With the 3 methods, namely, synthetic chemistry, spectroscopy, and theoretical calculation as the pillars of our science, we expand upon elements chemistry in an interdisciplinary manner as we meet the challenges of elucidating life phenomena and creating a new materials science.

 

Developing new reactions and designing/producing new materials based on computational chemistry and theoretical chemistry (Adopted for the cover of Chemistry: A European Journal)

Life sciences and materials science that open new frontiers in basic organic chemistry and elemental chemistry

Laboratory of Medicinal Plant Chemistry (Experimental Station for Medicinal Plant Studies)

https://www.f.u-tokyo.ac.jp/~oriharay/index.htm
Prof.：I. Abe

An overall analysis is made of the old-yet-new drugs known as "medicinal plants" (crude drugs) to develop new ways of using them (utilizing the resources in the Experimental Station for Medicinal Plant Studies)

Research Topics

1. The cultivation of medicinal plants and tissue cultures
2. The production of useful secondary metabolites, using plant tissue culture technology
3. Chemistry and biosynthesis of plant-derived biologically active substances

Since prehistoric times, plants have been the principal material used as drugs by humankind. Many have fallen by the wayside through a long process of trial and error (human experiments), and the ones that remain can be considered the crude drugs of the present day. In recent years, the percentage of all drugs accounted for by antibiotics and biologics has increased, but the importance of plant-derived pharmaceuticals is by no means diminished and has led to the discovery of new drugs such as Taxol and vinblastine. Thus, the study of medicinal plants is by no means completed, and is continuing to evolve.
The Experimental Station for Medicinal Plant Studies, formally established in 1973, is located adjacent to the Kemigawa Athletic Ground. The saplings transplanted there back then have grown large and now form a dense enclosure of trees around the garden.
At the research lab in Hongo, we conduct research on the production of useful secondary metabolites using plant tissue culture technologies (from the induction of culture cells to the production of substances). Some of the research topics we are currently pursuing are the biosynthesis of diterpene constituents from Gymnosperm plant cultured cells, the production and biosynthesis of diterpene alkaloids using cultured tissue of monkshood, the production and biosynthesis of phenylethanoids using cultured cells of olive, and the production of biologically active constituents of Egyptian medicinal plants by means of plant tissue culture technologies.

Aconitum japonicum cultured root

The sweetener glycyrrhizin is contained in the roots and stolons of Glycyrrhiza uralensis Fisher

Laboratory of Bioanalytical Chemistry

https://bunseki.f.u-tokyo.ac.jp/index_e.html
Prof（concurrent). : Y. Urano

We measure the functions of biomolecules at the level of a single molecule to elucidate vital functions

Research Topics

1. Research on the principles of action by which biomolecular machines such as molecular chaperonin and ribosomes operate
2. Single-molecule fluorescence imaging of intracellular mRNA processing and transport
3. Development of micro nanodevices for analyzing the functions and interactions of biomolecules

In order to understand living organisms, it is necessary to conduct research at a variety of different levels. The lowest level is that at which biomolecules such as proteins and DNA work. When these come together, biological supramolecules, cells, organs, and the like are created, while at the higher end, individual organisms, societies, and ecosystems are constituted. We focus on the level of the smallest unit, the "biomolecule," together with the level of the "cell," at which life functions are first expressed, to find answers to questions like "By what mechanisms do biomolecules function?" and "When they aggregate, what kinds of systems do they construct?"　Concretely speaking, we bind a fluorescent dye to a single biomolecule and observe it with a sensitive fluorescence microscope. Some biomolecules can exhibit their functions even at the level of the single molecule. For example, the motor protein known as kinesin moves on rail proteins called microtubules. Humankind does not at this point in time possess the technology for creating this kind of molecular machine, but we believe that humankind will be able to make this kind of molecular machine in the near future through research on the motor protein. On the other hand, self-assembly of a variety of different biomolecules creates complex systems which differ greatly from manmade ones. By researching such biological systems, we close in on the mysteries of life.

Fluorescence microscope system for imaging single molecules within living cells

The principle of single-molecule imaging of enzyme reaction (ATPase) using evanescent illumination

Laboratory of Physical Chemistry

https://biophys.f.u-tokyo.ac.jp/en
Prof. : K. Takeuchi
Lecturer : Y. Kofuku
Assist. Prof. : Y. Tokunaga
Project Assist. Prof.：Y. Toyama

Approaching life from dynamic structural information obtained by original NMR strategies.

Research Topics
    1. Functional mechanism of biologically and pharmacologically important proteins based on dynamic structural information.
    2. Functional mechanism of biomolecules that regulate signal transduction and energy metabolism based on interaction analysis.
    3. Development of NMR techniques to analyze the structure and dynamics of high-molecular-weight proteins.
    4. Strategies to reproduce the functional environment of biomolecules and sophisticated stable isotope labeling methods.
    5. In-cell NMR and its application to intracellular drug discovery.

　The structural information of proteins plays a vital role in elucidating biological functions and their applications to drug discovery. In addition, it has become clear that proteins do not adopt only a single conformation but also an equilibrium among multiple functional conformations. These dynamic properties are directly related to the expression and regulation of protein functions.
　In our lab, we analyze the structure and dynamics of proteins mainly by using NMR to understand biological phenomena through elucidating the functional mechanisms of biomolecules. We focus on membrane proteins, such as G-protein-coupled receptors (GPCRs) and transporters, as well as macro-molecules that regulate intra-cellular signal transduction and energy metabolism, which are important in biological and pharmaceutical sciences. By developing original NMR methods, we have obtained structure and dynamics information of the macromolecules of interest that were previously difficult to analyze. In addition, we are developing an in-cell NMR strategy to analyze the structure and dynamics of proteins in the actual cellular environment and extending these strategies to establish intracellular drug discovery.

Fig. 1 Biological phenomena elucidated by dynamic structural analysis using NMR in our laboratory. (A) Structural equilibrium determines (B) transcriptional activity of multidrug-resistant transcription factors (Proc Natl Acad Sci (2019) 116, 19963. (C) Drug efficacy of each ligand of GPCR (β2 adrenergic receptor) (NatCommun (2012) 3, 1045: Angew Chem Intl Ed (2014), 53, 13376).

Fig. 2 Novel NMR experiments developed in our laboratory and their application to mAb (J Med Chem. (2020) 63, 5360: Nat Methods. (2019) 16, 333).

Laboratory of Health Chemistry

https://sites.google.com/view/eiseikagaku-en/
Prof. : J. Aoki
Assoc. Prof. : N. Kono
Assist. Prof.：K.Kano
Assist. Prof.：Y. Shimanaka
Project Assist. Prof.：J. Omi

Exploration of new functions for biomembranes and their constituent lipids

Research Topics

1. Reveal the physiological and pathological functions of lysophospholipids that work via GPCR
2. Discover new bioactive lipids and their receptors
3. Identify novel molecules involved in phospholipid biosynthesis and homeostasis, and elucidating their functions.

Biological membranes are composed of more than 1,000 lipid molecular species, and each of them is thought to have a specific function. Recently, some functions of lipids have been elucidated, and it is becoming clear that lipid molecules play essential roles in physiological situations such as reproduction, development, angiogenesis, and cell proliferation, and in pathological processes such as cancer and fibrosis development. On the other hand, the recent progress of mass spectrometry has revealed that there are more lipid molecules with unknown functions in the body. Unlike proteins, lipid molecules are not encoded by genes and lipid synthesis usually involves multiple proteins. Therefore, investigating the function of lipids is much more complicated than that of proteins. We are tackling to clarify the functions of various phospholipids by using the latest technologies including mass spectrometry and mass spectrometry imaging. Our research results are promising to be applied to drug discovery and biomarker discovery.

The functions of membrane lipids

Lipid-related diseases

Laboratory of Physiological Chemistry

https://seirikagaku.f.u-tokyo.ac.jp
Prof. : D. Kitagawa
Lecturer : M. Fukuyama
Project Lecturer : S. Hata
Assist. Prof. : T. Chinen
Assist. Prof.：S. Yamamoto

Mechanisms of cell division and their application to drug development

Research Topics

1. Mechanisms of centrosome duplication and its theoretical model
2. Mechanisms of cell division regulated by divergent molecular machineries
3. Identification and characterization of non-coding RNAs that regulate cell division
4. Comparative cancer cell biology and its application to anticancer drug development
5. Forward genetic analysis of cell-cell communication with human cells

Our laboratory mainly focuses on understanding the mechanisms of cell division, with aparticular emphasis on the molecular basis and theoretical model of centrosome duplication. We are also interested in elucidating how divergent molecular machineries, including a protein complex and protein-lncRNA complex, regulate somatic and meiotic cell division. Based on these studies,we then explore a new approach to develop anovel anti-cancer therapy.To this end, we currently use the combination of innovative and multi-disciplinary methods including molecular biology, biochemistry, biophysics, structuralbiology, genetics, computer simulation and cellbiology.
Furthermore, to understand molecular mechanisms and basic principles underlying a wider range of biological phenomena in vivo, we are also trying to establish a forward genetic approach with in vitro reconstitution of human cell-cell communication.

Bipolar spindle formation in mitotic HeLa cells. Control (left panel) and a cell defective in forming a proper mitotic spindle and chromosome segregation (right panel).

Centriole duplication and structure. An image obtained by super-resolution microscopy: centriole wall in green, cartwheel structures in red.

Laboratory of Molecular Biology

https://molbio.f.u-tokyo.ac.jp
Prof. : Y. Gotoh
Assoc. Prof. : D. Kawaguchi
Project Assoc. Prof. : K. Oishi
Assist. Prof. : T. Kuniya
Project Assist. Prof. : H. Sugishita

Molecular studies of brain development, homeostasis and disease

Research Topics

1. Molecular mechanisms responsible for the regulation of neural stem-progenitor cell fate during development and adulthood 
2. Epigenetic regulation of cell fate determination
3. Dysregulation of neural development associated with neurodevelopmental disorders

How does a cell determine its fate? This is a fundamental question in understanding multicellular organisms. Our laboratory aims to understand development of the mammalian brain from the viewpoint of cell fate determination at the molecular level. The brain, the organ responsible for our thoughts and actions, processes sophisticated information through extremely complex neural circuits. The mammalian brain is formed during development by the repeated proliferation and differentiation of neural stemprogenitor cells (NSCs), which give rise to various types of neurons and glial cells, and by the proper positioning of these progeny cells and circuit maturation. The brain contains many regions that perform different functions, and NSCs are responsible for the generation and construction of functional elements specific to each region. In addition, a specific subset of NSCs persists in the adult mouse brain and continues to produce neurons throughout life, with these neurons being thought to play essential roles in learning, memory, recovery from stress, and innate behaviors. We are particularly interested in temporal and spatial cues as well as epigenetic regulation of gene expression and nuclear chromatin architecture that underlie proper brain development and function. For example, we are currently investigating the contribution of chromatin and epigenome regulation to the developmental stage–dependent control of NSC fate as well as to the history-dependent plasticity of neural circuits. We are also investigating the molecular basis of neurodevelopmental disorders with the use of mouse models. We hope to contribute to a better understanding of the principles of normal brain development and of the pathogenesis of developmental brain abnormalities.

Laboratory of Genetics

https://idenut.f.u-tokyo.ac.jp
Assoc. Prof. : Y. Nakajima
Assist. Prof. : N Shinoda

Molecular logic underlying the formation and maintenance of cell society in the body 

Research Topics

1. Regulatory mechanisms of non-apoptotic caspase
2. Metabolic regulation of development, regeneration, growth and aging
3. Molecular mechanisms of phenotype expressivity
4. Mechanisms of tissue size control during development 
5. Cellular plasticity in tissue homeostasis and environmental responses

Programmed cell death functions in dynamic tissue formation and remodeling. We have revealed that in the embryonic development, or aging process, caspases are activated by physiological stresses and exert not only apoptosis but also regulatory functions. We aim to reveal how caspase and metabolisms are involved in the determination of phenotype expressivity during development, growth, regeneration and aging. We also study the mechanisms of tissue size control during development and cellular plasticity in tissue homeostasis and environmental responses. We believe that our research would stimulate and encourage students and researchers to have the breadth of vision for life science research and provide new insights into the molecular logic underlying the formation and maintenance of cell society in the body.

Fig. 1: Caspases are activated in cells exposed to various environmental stresses (Left). To monitor the activation state of caspase in live cells, we generated a genetically encoded sensor for caspase activation based on FRET, named SCAT3 (Right). Color change from red to blue reflects the activation state of caspase (Left bottom). Fig. 2: Birth and selection by cell death of neural precursor cells during the development of Drosophila sensory organ Fig. 3: Live-imaging of apoptosis in the neural tube closure of mouse brain Fig. 4: Genetic labeling and manipulation of olfactory projection neurons in Drosophila brain

Laboratory of Cell Signaling

https://saijyou.f.u-tokyo.ac.jp/en/index.html
Prof. : A. Takahashi
Assist. Prof. : T. Fujisawa

From signal transduction to drug discovery

Research Topics

1. Exploration of novel signaling molecules involved in cell death and stress responses
2. Molecular mechanisms of pathogenesis induced by dysfunction of stress signaling

The Laboratory of Cell Signaling has been focusing on analyses of the intracellular signal transduction, through which we seek to elucidate molecular basis of human diseases and identify novel drug targets. Our current research mainly focuses on the pathophysiological roles of stress responsive signals in various diseases such as cancers, immune disorders, cardiovascular diseases and neurodegenerative diseases. In addition to molecular genetic tools such as mice, flies and worms as well as basic experimental techniques from molecular cloning to protein biochemistry, we always incorporate novel analytic technologies such as mass spectrometry-based proteomic analysis and genome-wide RNAi screening systems into our research exploring"target molecules and molecular mechanisms". By taking advantage of such experimental approaches, we aim to open up new fields in pharmaceutical sciences with paying attention to whole body physiology, diseases and drug discovery.

MAP kinase pathways in mammals

Analysis of stress signaling at levels of molecules, cells and bodies

Laboratory of Protein Metabolism

https://tanpaku.f.u-tokyo.ac.jp/
Prof. : S. Murata
Assoc. Prof. : J. Hamazaki
Assist. Prof. : Y. Shibata

Elucidating various biological phenomena controlled by proteolysis

Research Topics

1. The action mechanisms of the proteasome, a multisubunit macromolecular complex responsible for regulated protein degradation in eukaryotic cells
2. Proteasome dysfunction in human diseases (senescence, malignant tumors, inflammation, neurodegeneration)
3. The mechanism of maintenance of protein homeostasis by the ubiquitin-proteasome system

The proteasome is a supramolecular proteolytic apparatus that exists in all eukaryotic cells. The proteasome plays pivotal roles in various cellular functions by selectively degrading ubiquitinated proteins. It is also central to the maintenance of protein homeostasis (proteostasis). In recent years, it has become evident that the impairment of proteostasis is a hallmark of senescence, and the decline of proteasome function is drawing attention as one of the primary factors. Indeed, it has been shown that age-associated diseases develop as proteasome function declines with age, and that artificial increase in proteasome activity prolongs the healthy lifespan in nematodes and Drosophila. However, in mammals, means to enhance proteasome function has not been found at present. This is because in mammals the proteasome is controlled more complicatedly and because the mechanisms by which the proteasome function decreases with aging and by which a decrease in proteasome function causes senescence are not understood. On the other hand, it has become clear that inhibition of proteasome function is an important therapeutic strategy in malignant tumors where proteasome hyperactivity is observed.
The ultimate goal of Laboratory of Protein Metabolism is to create a method of intervention in pathologies involving proteasome dysfunction. To this end, we are researching detailed mechanisms of action and regulation of the proteasome by using techniques such as molecular and cell biology, comprehensive gene screening, proteomics, and mouse genetics.

Laboratory of Computational Biology and Bioinformatics

https://carushi.github.io/cb_lab/index_en.html
Assoc. Prof. : R. Kawaguchi

Decoding how living organisms shape their future behaviors by orchestrating body cells through the dynamic processing of external and internal information signals

Research Topics

1. Understanding the diversity of cellular and organismal phenotypic variations arising from discrete genetic information
2. Elucidating the evolutionary trajectory of intracellular multi-omics regulatory networks
3. Bridging the gap between biological big data and mathematical models using cutting-edge techniques of information science                                                                       

We, the Laboratory of Computational Biology and Bioinformatics, conduct research in life andpharmaceutical sciences from the perspective of how biological systems store, receive, and transmitinformation. The advancement of experimental techniques in recent years has enabled the acquisition oflarge-scale, high-dimensional biological data, necessitating new computational approaches to reveal theunderlying regulatory mechanisms behind data. Our goal is to develop innovative data analysis methodsbased on information science, statistics, and mathematical sciences, ultimately leading to the discoveryof complex biological systems and the development of drugs to manipulate them.Our research focuses on understanding cellular andorganismal phenotypic diversity originated from bothheritable and non-heritable information. Usingcomputational methods based on statistics andmachine learning, we aim to construct gene andmolecular interaction networks from multi-omics data,and predict cellular responses to external stimuli ordrug treatments under untested environmentalconditions. Additionally, we work on bridging bigdata-driven models with interpretable mathematicalmodels to enhance human comprehension andfacilitate intuitive visualization.

Laboratory of Pathology and Development(Institute for Quantitative Biosciences )

https://webpark2349/
Prof. : Y. Okada

Investigation of chromatin dynamics in germ cells

Research Topics

1. Profiling sperm-retained histones
2. Elucidating the sperm chromatin structure
3. Investigation of the machamism of histone retentaion in sperm during histoneprotamine exhange

“Neuronal cells are who you are, while germ cells are where you came from.”- This is the word by a leading scientist in the field of germ cell research. Somatic cells including neuronal cells compose ourselves, while germ cells play transgenerational roles. Recently, scientists demonstrated that not only DNAs but also certain non-DNA factors can be transgenerationally transferred from ancestors to progenies. The substance of this is non-DNA material is supposed to “epigenome” such as chromatin and small RNAs, although the real entity hasn’t been determined. For now, the most possible idea is that the parental epigenetic information in their germ cells is altered upon stress responses and transferred to the progeny by fertilization. In our laboratory, we are investigating how epigenetic information is established in germ cells (especially in male germ cells) and altered upon various stress responses using biochemical, molecular biological, and genomic approaches. In addition, we are trying to utilize our research outcome for sperm quality control in Assisted Reproductive Technologies (ART). 

Laboratory of Molecular Neurobiology(Institute for Quantitative Biosciences )

https://www.kishilab.iqb.u-tokyo.ac.jp/en
Assoc. Prof. : Y. Kishi

Understanding how the brain functions through epigenetic analysis

Research Topics
      1. Epigenetics analysis of brain cells to understand alterations in brain function under aging, stress, and psychiatric disorder conditions
      2. Epigenome editing of neurons to improve brain function   

Our genetic information is encoded in our genomic DNA. Several mechanisms are used to properly identify and access the necessary genetic information contained within our three billion base pairs of DNA. One of these mechanisms is epigenetic regulation. Through epigenetic regulation, chemical modifications on DNA and histones—such as methylation and acetylation—function as “bookmarks,” resulting in the expression of only the necessary genes.

These epigenetic “bookmarks” are modified in response to the cell’s previous exposures to stimuli and experiences. In other words, epigenetic regulation functions as the memory system of cells. The question then becomes, what role does epigenetics play in the brain, which is the memory system of individuals?

In our laboratory, we are working to understand the mysteries of the brain through epigenetic analysis by combining the biochemical, molecular biological, and bioinformatics technologies needed to carry out the latest genomic analysis with the genetic and neuroscience technologies necessary to analyze brain function. Through this research, we aim to understand the basis of changes in brain function caused by aging, stress, and psychiatric disorders.


 

Social Cooperation Program of Targeted Protein Degradation

https://tpd.f.u-tokyo.ac.jp/en/index.html
Prof（concurrent). : S. Murata
 

Inducing targeted protein degradation by chemical compounds

Research Topics

1. Development of new technologies to induce protein degradation
2. Development of SNIPER compounds that degrade disease causative proteins

As the mechanisms of various diseases are better understood at the molecular level, it will become possible to develop molecular target drugs that specifically inhibit pathogenic proteins. With the current drug discovery technologies, however, it is not possible to develop such drugs against all pathogenic proteins. Especially, most of the intracellular proteins without enzymatic activity have been considered undruggable. Targeted protein degradation is a promising approach for suppressing such undruggable targets. Chimeric compounds such as PROTACs and SNIPERs are attracting attention because they allow us to develop novel drugs that degrade proteins of your interest. In our laboratory, we have developed a series of SNIPER compounds that degrade various target proteins. SNIPERs recruit IAP ubiquitin ligases to target proteins for ubiquitylation and proteasomal degradation. We are currently developing new technologies to induce protein degradation, which include cancer-specific or tissue-specific degradation of target proteins. We are also developing new compounds that degrade disease causative proteins.
 

Laboratory of RNP Synthetic Biology and Biotechnology（Institute for Quantitative Biosciences)

Prof. : H. Saito
Lecturer.：T. Yoshii

Empowering new life systems through synthetic biology and bioengineering

Research Topics

1. Basic biology and drug discovery based on RNA and RNP
2. Synthetic biology and bioengineering for gene expression and cell-fate control
3. Creation of artificial biomolecules and living matters for medical applications

In our laboratory, we delve into the fascinating world of RNA and RNA-Protein complexes (RNPs), pivotal elements in myriad life processes. Our research is dedicated to unraveling the mysteries of RNA and RNP interactions, aiming to deepen our understanding of life systems, discover new biological phenomena, and pioneer groundbreaking technologies. RNPs, formed through the recognition of RNA sequences and structures by proteins, are central to the cellular mechanisms controlling gene expression and intracellular localization. By elucidating the sequences and structures involved in RNP interactions, along with their molecular mechanisms, we unlock the potential to artificially modify the functions and formations of RNA and RNP complexes. This capability opens up exciting possibilities for manipulating cellular functions at will, creating artificial RNAs and RNPs with novel functions, and exploring the interactions between RNA and various molecules “X” (RNX) as a foundation for understanding and creating new biomolecules and life systems (RNX Synthetic Biology). We believe in the importance of integrating interdisciplinary technologies and developing new ones to forge new research fields. By merging techniques and knowledge from synthetic biology, evolutionary engineering, informatics, and biophysical chemistry, we aim to develop new technologies for understanding and controlling life systems. Leveraging our unique technologies, we strive to elucidate the mechanisms behind RNAbased life systems, contributing to the life sciences and paving the way for new pharmaceutical developments. Our lab is not just a place of research but a crucible of innovation, where we challenge the boundaries of science to create a future where the mysteries of life are not just understood but harnessed.

Laboratory of Protein Dynamics（Division of Protein Metabolism，The Institute of Medical Science)

Prof.：Y. Saeki
Assoc. Prof. : T. Kobayashi

Understanding diverse cellular functions through protein dynamics

Research Topics

1. Regulation of Cellular Functions by the Ubiquitin Code
2. Stress adapation mechanisms by liquid-liquid phase separation
3. Proteostasis of adult neural stem cells

The Laboratory of Protein Dynamics studies how the cellular proteome is shaped and maintained in response to changes in the cellular environment. It has become clear that dysregulation of proteostasis has emerged as a key factor contributing to a range of pathologies, including neurodegenerative diseases. The ubiquitin system plays a pivotal role in proteostasis and proteome remodeling by spatiotemporally regulating diverse biological phenomena such as protein degradation, cellular localization, and protein-protein interactions. Behind the diverse functions of ubiquitin modifications, we have shown that higher-order structures of ubiquitin chains act as “ubiquitin code”. More recently, we have also discovered a ubiquitin code drives liquid-liquid phase separation with specific ubiquitin decoders. Additionally, our laboratory focuses on neural stem cell proteostasis, in which protein degradation plays a crucial role in reactivating neural stem cells from dormancy to proliferation. Thus, our goal is to uncover the impact of proteome remodeling and proteostasis on disease pathogenesis and contribute to drug discovery.  

Laboratory of Nucleic Acids Research（Isotope Science Center）

Prof.：N. Akimitsu

Investigation of the molecular functions of nucleic acids (especially, RNA), and development of nucleic acid therapeutics

Research Topics

1. Investigation of molecular mechanisms of noncoding RNAs for the gene regulation.
2. Investigation of physiological and pathological roles of membrane-less organelle.
3. Development of basic technology to control nucleic acid medicine.
4. Integrative research on radiopharmaceutical and nucleic acid drug

Nucleic acids such as DNA and RNA play a central role in gene expression flow. This laboratory has been focusing on investigation of roles of nucleic acids. We have revealed that long noncoding RNAs regulate the cellular responses against stresses such as pathogenic infection, heat shock, and DNA damage. We also investigate physiological and pathological roles of membrane-less organelle formed by nucleic acids and RNA binding proteins. In addition, we have revealed the biological significances of RNA turnover regulated by RNA binding proteins through omics-based approaches. Based on these achievement, we also develop technologies for nucleic acid therapeutics. To develop the designer RNAs, we are also working on radiation theranostics using nucleic acid aptamers, integrating radiopharmaceutical and nucleic acid drug discovery.