Idea of the Institute

Transcription

1 Institute for Molecular and Cellular Regulation National University Corporation Gunma University Department of Molecular and Cellular Biology Department of Molecular Medicine Biosignal Genome Resource Center Metabolic Signal Reseach Center Biosignal Reseach Center 2016 Tenure-track Assistant Professor Gunma University Initiative for Advanced Research (GIAR)

2 Idea of the Institute

3 Contents Idea of the Institute Director s Message Organization & Academic Staff Institute Activities Research Activities/Research Funds Introduction of the Departments Department of Molecular and Cellular Biology Laboratory of Molecular Genetics Laboratory of Molecular Traffic Department of Molecular Medicine Laboratory of Cell Physiology Laboratory of Molecular Endocrinology and Metabolism Laboratory of Developmental Biology and Metabolism Laboratory of Medical Neuroscience Biosignal Genome Resource Center Laboratory of Genome Sciences Metabolic Signal Research Center Laboratory of Metabolic Signal Biosignal Research Center Laboratory of Secretion Biology Laboratory of Molecular Membrane Biology Tenure-track Assistant Professor Tenure-track Assistant Professor Gunma University Initiative for Advanced Research (GIAR) Laboratory of Cell Signaling Brief History Facilities

4 Director s Message Director/Tetsuro Izumi 4

5 Organization & Academic Staff 5

6 Institute for Molecular and Cellular Regulation, Gunma University Izumi, Tetsuro 6

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8 Cell Metabolism Nature Medicine Science Cell Nature Genetics EMBO J. Nature Nature Commun. Proc.Natl.Acad.Sci.USA Cell Leukemia Diabetes Diabetologia Endocrinology Traffic 8

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13 Research Activities Research Funds 13

14 Staff Professor Takayuki Yamashita Assistant Professor Tsukasa Oda Assistant Professor Takayuki Sekimoto Research fellow Kiminori Kurashima Assistant Technician Kyoko Tomizawa Graduate StudentDept of Health Ruri Nakamura Graduate StudentDept of Health Miyako Matsuda Medical StudentMD & PhD course Satoko Sunaga 14

15 Department of Molecular and Cellular Biology Laboratory of Molecular Genetics Specific aims e aim to elucidate te role of stress responses in carcinogenesis and cellular senescence and to identify diagnostic iomarers and terapeutic targets in tese cellular processes errorprone family N polymerases potentially promoting genomic instaility in tumor cells ur recent findings suggest tat tese polymerases participate in te oncogeneinduced aerrant replication Heat Shock Factor (HSF) 1-mediated regulation of cellular senescence transcriptionally activates eat oc Response in response to proteindamaging stress e recently found tat acute depletion of induces cellular senescence in nonstressed cells in a prdependent manner Interestingly depletion also induces cellular senescence in pr tumor cells ese findings suggest tat regulates senescence troug redundant patays independently of te eat soc response Mol Cell Biol Genes and Environment Mol Cell Biol Mol Cell On-going projects variety of N andor proteindamaging agents derived from te environment and cell metaolism activate diverse stress responses inducing genomic instaility and cellular senescence ic plays a critical role in tumor development and organismal aging respectively Importantly activated oncogenes also promote genomic instailitytumor progression and cellular senescencetumor suppression in a paradoical manner troug te oncogenic stress response Oncogenic stress-induced genomic instability and cellular senescence ncogeneinduced anormal N replication and suseuent N damage promote tese processes troug poorly understood mecanisms e previously reported tat te cancer caperone sp activates 15

16 Staff Professor Ken Sato Associate Professor Taichi Hara Assistant Professor Noukatsu Morooka Technical Officer Hisae Koayashi Research ellow kuko Maeima Research ellow Yasuharu Kushida Assistant Technician Rika Hirai Assistant Technician Tomoko Akuzawa Assistant Technician Mayumi Seto Graduate Student Keiko Saegusa Graduate Student Ryosuke Konuma Medical StudentMDphD course Ai Kawaguchi Medical StudentMDphD course Yuki Shiusawa Medical StudentMDphD course Takehiro Nakamura Medical StudentMDphD course noya soe rmerme 16

17 Department of Molecular and Cellular Biology Laboratory of Molecular raffic C. elegans C. elegans C. elegans C. elegans Specific aims Memrane trafficing plays essential roles not only in secretion and nutrient uptae ut also in various pysiological processes suc as tose involving te endocrine system metaolic system and nervous system and tose occurring during development in animals In our laoratory e study te molecular mecanisms and pysiological functions of memrane trafficing in multicellular organisms y using te nematode Caenorhabditis elegans and mice as model systems In addition e study te molecular mecanisms underlying proteinmisfolding diseases in ic anormal memrane proteins accumulate in te endoplasmic reticulum R in order to discover ne targets for te treatment of suc diseases On-going projects nalysis of molecular mechanisms underlying lo-density lipoprotein trafficking in C. elegans odensity lipoproteinconsists of core proteins and lipids suc as colesterol In mammals is recognied y te receptor on te cell surface and is ten taen up y cells via receptormediated endocytosis is process is important for removing from te lood and maintaining a normal level of Interestingly te caracteristics of C elegans yol are uite similar to tose of mammalian In C elegans yol is secreted from te intestine and taen up y oocytes via receptormediated endocytosis e are studying te molecular mecanism underlying trafficing y utiliing te advanced genetic tecniues tat are availale for C elegans e are also studying te pysiological functions of mammalian omologues of te genes identified y C elegans genetic studies y generating nocout mice nalysis of physiological functions of membrane trafficking during deelopment o elucidate te pysiological functions of memrane trafficing during development in animals e are utiliing C elegans as a model system for te study of oogenesis fertiliation and emryogenesis e ave identified a novel type of developmentally regulated cortical granules in C elegans oocytes e are trying to clarify te molecular mecanisms underlying te iogenesis and eocytosis of te cortical granules as a model of regulated secretion Recently e also found tat fertiliationinduced autopagy is responsile for selective degradation of paternal mitocondria and terey of maternal ineritance of mitocondrial N e are no studying tese penomena during development in mammals y using a live imaging system of mouse emryos nalysis of the molecular mechanisms underlying retention of disease-associated membrane proteins e are studying te molecular mecanisms underlying proteinmisfolding diseases in ic anormal memrane proteins accumulate in te R e are also trying to identify ne terapeutic targets for suc diseases C. elegans Dev. Cell Sci Rep C. elegans Mol Biol Cell. Sci Rep. Development Sci Rep. Biochim Biophys Acta MCR Traffic C. elegansscience Caenorhabditis elegans Mol Biol Cell 17

18 Staff Associate Professor Hiroshi Shiata Assistant Professor Masahiro Nagasawa Assistant Professor Yuko Nakagawa Secretary Mayumi Odagiri Resaerch Scientist Kimitaka Kogure Research ellow oahn Medina Graduate Student i ongfei 18

19 Department of Molecular Medicine Laboratory of ell ysioloy Specific aims lucidation of actions and mecanism of actions of ormones grot factors and cytoines involved in metaolic regulation tissue repair and regeneration and teir pysiological and patopysiological roles in relation to diaetes oesity cancer and tissue firosis On-going projects ction and mechanism of actions of hormones groth factors and differentiation factors e are investigating te actions and mecanism of actions of various ormones grot factors and differentiation factors e are also studying te pysiological and patopysiological roles of tese factors in metaolic disorders and tissue firosis ignal transduction patays activated y te seet taste receptor eet taste receptor epressed in te taste ud is a dimer of R and R It is also epressed in enteroendocrine cells pancreatic cells and adipocytes e found tat various agonists for te seet taste receptor induce diverse canges in te second messengers suc as calcium cyclic M and diacylglycerol e are no investigating te role of te seet taste receptor in pancreatic cells and adipocytes Calciumpermeale cannel R e ave een studying te regulation of a calciumpermeale cation cannel R e are particularly interested in te trafficing of R and pysiological role of trafficing of R echanism of action of insulin on glucose transport Insulin stimulates glucose transport in adipocytes and muscles y promoting translocation of a glucose transporter GU from te intracellular storage pool to te plasma memrane e ave een studying te mecanism of insulinregulated GU trafficing in adipocytes Currently e are studying te mecanism of insulininduced donregulation of GU in adipocytes Physiol Rep J Endocrinol Biol Pharm Bull J Diab Invest Liver Int Mol Cell Endocrinol J Biol Chem 19

20 Staff Professor Tetsuro zumi Associate Professor Katsuhide Okunishi Assistant Professor Kohichi Matsunaga Assistant Professor Koichi Mizuno Assistant Professor Hao ang Technical Officer Takeshi shigome Assistant Technician Takae Nara Assistant Technician ri Koayashi lerical Assistant Sachiko Shigoka Graduate Student ushun an Graduate Student Yun u Graduate Student Keii Hoshino 20

21 Department of Molecular Medicine Laboratory of Molecular nocrinoloy an Metabolis a l Cel Cell l Cell l e l l Cell l l Cell el Cell ll l Cell Cln nes Cell ea l l Cell Cell Cln nesaees aeesa ene aees e Specific aims Mecanism for regulated eocytosis of secretory granules e are interested in te molecular mecanism of secretory granule eocytosis e are investigating te functional and mecanical relationsip among docing priming and fusion of insulin granules to te plasma memrane in living eta cells epressing multiple fluorescently laeled proteins urtermore e are studying in vitro and in vivo function of Ra and its effectors eopilins ic regulate various trafficing steps of secretory vesicles especially in te fields of endocrinology metaolism and immunology Genetic analysis of diaetes and oesity in rodent models e aim to clarify te genetic alterations tat are responsile for diaetes and oesity in rodent disease models e are currently investigating te molecular mecanism of pancreatic etacell dysfunction and tat of anormal fat accumulation On-going projects Morpological analyses of intracellular trafficing suc as docing priming and fusion of secretory granules in living cells y confocal total internal reflection fluorescence and electron microscopes In vitro and in vivo functional analyses of te small Gases Raa and Ra and teir effectors eopilins in regulated eocytosis ffects of impaired Ra systems on te patogenesis of immune respiratory and sin diseases Molecular mecanism of adipose fat accumulation in oesity especially focusing on te role of and its ligand Sci ep ell Sci Sci ep llergy lin mmunol FS 21

22 Staff Professor Yoshio uitani Associate Professor Takashi Sato Assistant Professor Ayako ukunaka hief Technician Masayuki Too Assistant Technician Asuka Suda Student Satoshi Kuranami Student Yoichiro Nishikawa 22

23 Department of Molecular Medicine Laboratory of eeloental ioloy an Metabolis Our research e dysfunction of pancreatic cells ron adipocytes and enterocytes can cause diaetes and metaolic syndrome ur goal is to elucidate te molecular mecanism involved in te maintenance of omeostasis of tese igerorder function cells ic is te ey to glucose metaolism e aim to elucidate te mecanism of cellular omeostasis from a variety of viepoints including developmental iology inc iology autopagy and cell polarity y effectively utiliing genetically engineered mice urtermore using our findings from asic medical researc e aim to estalis a groundreaing treatment for diaetes and oesity On-going projects Research on the deelopmental iology of pancreatic cells unctional analysis of autophagy in lifestyleassociated diseases Analysis of zinc transporters inoled in the rowning of adipocytes Screening and functional analysis of molecules inoled in the regulation of enterocytes Shigihara N et al lin nest Sato T et al ell Sci Tamaki M et al lin nest ato et al ell Meta Sato T et al Nature ol ndocrinol iabetologia lin nest iochem iophyses ommun ell Sci iabetes lin nest iochem iophyses ommun ndocrinology roc atl cad Sci S 23

24 Staff Professor Akiko HAYASHTAKAG Associate Professor Koichi SATO Assistant Professor hihiro MOG Research ellow Takeyoshi ADA Research ellow Tsuyoshi HYAMA Research ellow Ayaka TOO Assistant Technician Mutsumi TAKANO Assistant Technician Mayumi NAKAMRA Assistant Technician mi HOSOYA Graduate Student D ukutoshi SHRA MDPhD ourse Student Takayuki MA MDPhD ourse Student Mari MAA isiting Scientist Norimitsu SK 24

25 Department of Molecular Medicine Laboratory of Meical euroscience Nature Specific aims rug discovery in neuropsyciatry as een limited to cemical modifications of compounds originally discovered serendipitously erefore more mecanismoriented strategies of drug discovery for neuropsyciatric disorders are aaited e deterioration of te neuronal circuit as attracted attention as te patopysiology of tese disorders and aerrant responses against te stress suc as oidative stress is no eing considered as a possile causal signaling in tese diseases us e aim to elucidate te diseaserelevant signaling patay y utiliing stateofart imaging tecniue eventually callenging to identify a novel terapeutic target for neuropsyciatric disorders On-going projects amination of neuronal stress response for te drug discovery of neuropsyciatric disorders ig e are performing te ig trougput in vitro screening system as ell as in vivo poton rain imaging of disease model so tat uantitative measurement of te synaptic deterioration and stressrelated metaolites are no eing investigated ogeter it eavioral assessment e aim to identify a novel terapeutic target for neuropsyciatric disorders isualiation of te diseaserelevant neurocircuits in te neuropsyciatric model mice us far te lins eteen synapses and rain functions ave een largely correlational ecause of lacs of a tecniue for manipulating individual synapse erefore e are engineering a novel synaptic optoproe arac to callenge te causal relationsip eteen synapse and iger rain functions arac specifically visualies te recently ritten synapse and ritten trace can e erased y lue ligt ig ayasiaagi et al Nature is novel ligtdependent tool of ynaptic optogenetics sould open up ne areas of rain researc and y etension sed ligt on te neural netors tat determine o e are ysiological and patopysiological roles of protonsensing GCRs e ave recently found tat GR family a group of GCRs sense etracellular p tracellular protons are approimately nm p under pysiological conditions ile it reac nm p in tumor iscemia and inflammation s suc te monitoring te etracellular p y te GR family memers triggers te diverse donstream signaling ic roustly regulates cellular manifestations y utiliing te gene engineering tecniues and parmacological intervention it novel GCR antagonists e callenge to elucidate te role of GR family in pysiological and patopysiological conditions ig ature roc atl cad Sci S eurochem at eurosci mmunol 25

26 Staff Professor zuho Hatada Assistant Professor Takuro Horii Research ellow Sumiyo Morita Research ellow Mihiro Shiuya Assistant Technician Mika Kimura Assistant Technician Naomi Terawaki Graduate Student M Takashi Yoda Assistant Technician Sumiko Nakano Assistant Technician hieko Shimizu lerical Assistant Hiromi wata 26

27 Biosignal Genome Resource Center Laboratory of Genoe ciences Specific aimes (Fig 1) pigenetics ors as a gene sitc ic is affected y life style e aims to clarify o life style affects tis gene sitc and cause diseases mecanisms of gene sitces evelopment of epigenome editing for epigenetic terapy On-going projects ienoe an iseases It as een long time after starting etensive genetic analysis of uman diseases oever some of te diseases are found not to e caused y genetic canges rater y te alteration of epigenome ic is te sitc of te genes errant canges of epigenome caused y life style results in several diseases lie diaetes It as also found tat mutations of genes involved in te gene sitc also cause tese diseases erefore e study nocout mice of tese genes to analye te effect of anomaly of te sitces mproement of Sas genome editing technology Recently a ne tecnology called CRIRCas for efficient genome editing system as een developed ig In tis system an endonuclease called Cas cleaves te target site it a sort RN guide RNcomplementary to te target nocout mice can e efficiently made y using tis system e are improving tis tecnology and also use it for maing disease model ere are to ays for tis purpose ne ay is to ust mae nocout mouse it tis tecnology nd te oter is to mae i model from normal i cells is i model is useful for disease researc ecause it can eclude te genetic variances eelopment of epigenome editing using Sas ere is no efficient metod for regulating N metylation of specific genes erefore it is impossile to demonstrate te role of specific metylation in diseases and tere is no epigenome terapy for a specific gene e are developing te epigenome editing using Cas deficient for nuclease activity ene ell Scientific eports ell ep p ermatol Scientific eports iabetes Sci ep os One 27

28 Staff Professor Tadahiro Kitamura Associate Professor Tsutomu Sasaki Assistant Professor Masaki Koayashi nit Assistant Professor Daisuke Kohno Research Associate Hiromi Hashimoto Post Doc ellow Osamu Kikuchi Post Doc ellow Shou Matsui Research Promotion Technician hihiro Osawa Research Promotion Technician Satoko Hashimoto Research Promotion Technician Hiroko Suzuki Graduate Student D Takayoshi Suga MDPhD course student Shouko uikawa MDPhD course student Yuri Numata 28

29 Metabolic Signal Research Center Laboratory of Metabolic inal Specific aimes e aim at clarifying te folloing topics troug te use of genetically engineered animal models Mecanisms for metaolic regulation at te molecular level Regulation of metaolismrelated genes y metaolic signals suc as ormones autonomic nervous systems and nutrients On-going projects e are trying to elucidate te molecular mecanism for pancreatic eta cell dysfunction in type diaetes y analying pancreasspecific genetically manipulated animals ig e are trying to clarify o metaolic signals regulate energy omeostasis in te ypotalamus at te molecular level ig and e are also investigating te molecular mecanism y ic plasma glucagon level is increased in type diaetes e are searcing for novel target genes and novel interacting proteins for o and irt y mass spectrometry e are developing a ne glucagon sandic I system and y using tis metod e are also reevaluating plasma glucagon levels in various conditions e are also investigating molecular mecanism for te etra eneficial effects of antidiaetes drugs toard controlling ody eigt and glucagon secretion e elieve tat tese studies ill lead to ne strategies to treat or prevent metaolic syndrome iol hem m hysiol egul ntegr omp hysiol ndcr ndcr iabetes eurosci ndocrinology iabetologia Obesity iabetologia ndocr at e ndocrinol ndocr iabetologia os One ature enet os One m hysiol -ndocrinol etab ndocrinology 29

30 Staff Associate Professor Seii Torii Research ellow hisato Kuota Graduate Student Ryosuke Shintoku Associate Professor Noukazu Nameki Associate Professor Keiichi Yamada Associate Professor Hiroaki Horiuchi Associate Professor Toshitada Yoshihara oint Research ellow Yoshiki Kaneko oint Research ellow Tomomi uisawa oint Research ellow Hiroshi Horikawa 30

31 Biosignal Research Center Laboratory of ecretion ioloy Specific aims o elucidate formation mecanisms for igly integrated functions of differentiated cells suc as pancreatic βcells and neuronal cells it use of molecular and cellular tecnical approaces On-going projects echanisms on peptide hormones secretion and secretory granule formation in endocrine cells eptide ormones syntesied at te endoplasmic reticulum are transported to te transgolgi netor GN ere tey are sorted and specifically targeted to secretory granules in neuroendocrine cells e found tat secretory granule protein pogrin inds to C and clatrin adaptors troug te luminal region and te cytoplasmic tail respectively suggesting tat tis transmemrane protein as a role in ormone sorting y providing a communication device eteen te granule lumen and te cytosol e furter investigate te regulatory secretion and degradation of peptide ormones using a recently developed multitag imaging system echanisms on groth surial and cell death in pancreatic -cells and neuronal cells e ave discovered tat pogrin functions as a regulatory mediator ridging eteen glucoseinsulin secretion and autocrine insulin signaling in te grot of pancreatic cells e are analying its pysiological role it use of te genetargeted mouse In addition e investigate te signaling patay of novel necrotic cell deat suc as necroptosis and ferroptosis it tumor cells or neuronal cells eelopment of fluorescent probes or anti-tumor compounds for inestigating arious diseases In a collaorative study it some engineering groups e are developing fluorescent or luminescent proes to dissect molecular mecanisms of dysfunction in cancer diaetes and oter diseases e demonstrated previously tat reactive oygen species are localied at autopagosomeslysosomes in a asal state and tey are eventually implicated to neuronal cell deat y cereral iscemia iabetes iochem Histochem ytochem raffic Histochem ytochem os One 31

32 Staff Associate Professor Miyuki Sato Assistant Technician Katsuya Sato 32

33 Biosignal Research Center Laboratory of Molecular Mebrane ioloy C elegans Specific aims uaryotic cells are composed of many memraneound organellesand sapes compositions and functions of tese organelles are dynamically regulated under various situations Memrane trafficing mediates transport eteen tem and determines te identity of eac organelle ic ases organellar dynamics e aim of our researc is to understand te molecular mecanisms and pysiological roles of memrane trafficing during animal development On-going projects utophagy of paternal mitochondria in C. elegans embryos uring te development of multicellular organisms eac cell canges its nature troug te remodeling of cellular constituents In particular fertiliation as te start of a ne life triggers dramatic cellular remodeling called te oocytetoygote emryo transition Using C elegans as a model system e ave son tat lysosomal patays are transiently activated in tis period and promote selective turnover of maternally and paternallyinerited proteins and organelles ig Upon fertiliation autopagy is locally induced around penetrating sperm and selectively degrades paternal mitocondria and Ms spermspecific organelles ig is autopagic degradation of te paternal mitocondria also eplains y mitocondrial N is maternally inerited e are trying to elucidate o paternal organelles are recognied and selectively engulfed y autopagosomes e are also interested in te pysiological and evolutional significance of tis autopagic degradation of paternal organelles ndocytic degradation of maternal membrane proteins in C. elegans embryos In addition to autopagy endocytosis is also upregulated after fertiliation and donregulates maternal memrane proteins troug te multivesicular ody Mpatay ig e found tat lined uiuitination of te sustrates is involved in tese processes ig e are trying to elucidate molecular mecanisms of tis selective endocytosis and te signaling patay tat induces uiuitination after fertiliation C. eleganse ell eelopment Caenorhabditis elegans ol iol ell ell es raffic C. elegans Science 33

34 Staff Assistant Professor Kazuto Ohashi 34

35 Tenure-track Assistant Professor enuretrac ssistant rofessor On-going projects ysiological roles of is produced from acteria to uman oever its pysiological function remains poorly understood I ill study te importance of in cell metaolism and pysiology using engineered yeast cells deleted for s Regulation mecanisms of s Considering te ioregulatory functions of te activity of s sould e controlled strictly I investigate te enymatic properties of s to understand te regulation mecanisms of syntesis Selected ublication ukaryotic ell ukaryotic ell Specific aims ynurenic acid is a tryptopan metaolite and is produced y ynurenine aminotransferases s interacts it cell surface receptors GR and Nmetylaspartate receptor ltered level of is associated it type diaetes and depression I aim to elucidate an intracellular function and metaolism of lso I epect tat my findings may contriute to understanding of tese diseases 35

36 Staff Associate Professor Satoshi Yoshida Assistant Professor Masakatsu Takaine Assistant Technician Miyoko Kitayama 36

37 Gunma University Initiative for Advanced ResearchGIAR Laboratory of ell inalin Specific aims ur la aims to understand molecular mecanism y ic cells respond to etracellular and intracellular signals e tae multifaceted approac comining iocemistry Genetics and Imaging to reveal mecanisms of action of ey signaling molecules suc as small Gases protein inases and pospatases J Cell Biol. J Cell Sci. J Cell Sci J Cell Sci. J Cell Biol. PNAS. Cell. PLoS Genet. J Cell Biol. On-going projects mecanism y ic mrc activates Ro Gase upon memrane stress o does ds protein inactivate pospatase upon stress Identification of a sensor molecule for intracellular pospate concentration and defining a role of polypospates in cellular energetics 37

38 Brief History Marc pril 1 pril pril May 23 uly pril Marc pril pril Marc May une ctoer 2 anuary ecemer pril une une Novemer 50 ctoer pril 38

39 Facilities 39

40 Institute for Molecular and Cellular Regulation Location of the Institute in Maebashi City Access Institute for Molecular and Cellular Regulation National University Corporation Gunma University