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Roles and regulation of lipid mediators

Research Project

Project/Area Number 12308034
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionThe University of Tokyo

Principal Investigator

SHIMIZU Takao  The University of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (80127092)

Co-Investigator(Kenkyū-buntansha) TANIGUCHI Masahiko  The University of Tokyo, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (70260346)
YOKOMIZO Takehiko  The University of Tokyo, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (60302840)
IZUMI Takashi  Gunma University, School of Medicine, Professor, 医学部, 教授 (70232361)
UOZUMI Naonori  The University of Tokyo, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (70313096)
ISHII Satoshi  The University of Tokyo, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (10300815)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥38,860,000 (Direct Cost: ¥33,700,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2002: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000)
Fiscal Year 2001: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2000: ¥16,500,000 (Direct Cost: ¥16,500,000)
KeywordsLipid mediators / arachidonic acid / lung fibrosis / inflammation / leukotrienes / phospholipase A2 / allegy / PAF / ホスホリバーゼA2 / 受容体 / 血小板活性化因子 / 神経可塑性 / 神経発生 / ホスホリパーゼA_2 / SNP / 生合成 / 脂質メディエータ / ロイコトリエンB4 / ロイコトリエンC / 5-リポキシゲナーゼ
Research Abstract

Upon cell stimulation, various types of phospholipases are activated, and a class of lipid mediators are produced. They play important role in self-defense and maintenance of homeostasis. In the last three years, we have carried out biochemical and genetic experiments, and obtained results as follows. The results have been published in almost 50 original articles and 6 reviews or book chapters.
1. Studies on cytosolic phospholipase A2 and related molecules.
cPLA2α-null mice showed impairment in synaptic plasticity and reproduction. The enzyme also plays important roles in inflammatory bone resorption, autoimmune arthritis, acute respiratory distress syndrome (ARDS) and bleomycin-induce pulmonary fibrosis. Thus, a selective cPLA2a inhibitor would be beneficial for these disorders. In addition to a subtype of cPLA2, we also found β, and γ subtypes of the enzyme. While β-subtype has Ca-sensitive C2 domain, g-subtype is activated by reactive oxygen species. We also found a novel truncated isoforms of cPLA2, specifically expressed in dentate gyrus by stimulation.
2. Characterization of leukotriene receptors.
We identified 4 different types of leukotriene receptors (BLT1, BLT2, CysLT1, and CysLT2). They are differently expressed in cells and tissues, by cognate promoter activations. We elucidated detailed signal transduction of these receptors, and established cell, either overexpressing or lacking these receptors. More systematic phenotype analyzes will be done by gene targeting of the mice.
3. Characterization of other types of receptors.
We analyzed PAF (platelet-activating factor) receptor, and further found that PAF is deeply involved in inflammatory responses, capacitation of sperm, and neuronal migration in cerebellar granular cells. We also identified the fate of PAF (its breakdown to lysophospholipids, and reacylation to 1-alky1-phospholipids). By SNP analyzes, we found a novel mutation in the third intracellular domain in asthmatic family.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Nagase, T.et al.: "Acute lung injury by sepsis and acid aspiration : a key role for cytosolic phospholipase A2"Nature Immunology. 1. 42-46 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kato, K.et al.: "Cell-specific transcriptional regulation of human leukotriene B4 receptor gene"Journal of Experimental Medicine. 192. 413-420 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokomizo, T.et al.: "A second leukotriene B4 receptor, BLT2. A therapeutic target in inflammation"Journal of Experimental Medicine. 192. 421-432 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ogasawara, H.et al.: "Characterization of mouse cysteinyl leukotriene receptors, mCysLT1 and mCysLT2"Journal of Biological Chemistry. 277. 18763-18768 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagase, T.et al.: "A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis"Nature medicine. 8. 480-484 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyaura, C.et al.: "An essential role of cytosolic phospholipase A2α in PGE2-mediated bone resorption associated with inflammation"Journal of Experimental Medicine. 197. 1303-1310 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hegen et al.: "Cytosolic phospholipase A2α deficient mice are resistant to collagen-induced arthritis."J.Exp.Med.. 197. 1297-1302 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyaura et al.: "An essential role of cytosolic phospholipase A2α in prostaglandin E2-mediated bone resorption associated with inflammation"J.Exp.Med.. 197. 1303-1310 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Asai,K. et al.: "Human group IVC phospholipase A2(cPLA2) : roles in the membrane remodeling and activation induced by oxidative stress"J.Biol.Chem.. 278. 8909-8914 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Taniguchi,M. et al.: "Distored odor maps in the olfactory bulb of semaphonn3A-deifcient mice"J.Neurosci.. 23. 1390-1397 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wong,DA et al.: "Discrete role for cytosolic phospholipase A2a in platelets : studies using single and double mutant mice of cytosolic and group llA-secretory phospholipase A2"J.Exp.Med.. 196. 349-357 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ogasawara,H. et al.: "Characterization of mouse cysteinyl leukotriene receptor, mCysLt1 and mCysLT2"J.Biol.Chem.. 277. 18763-18768 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagase,T. et al.: "A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis"Nature Med.. 8. 480-484 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohsima,N. et al.: "Receptor-dependent metabolism of platelet activating factor in murine macrophages"J.Biol.Chem.. 277. 9722-9727 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Stromgaard,K. et al.: "Ginkolide derivatives for photolabelling studies : preparation and phamacological evaluation"J.Med.Chem.. 45. 4038-4046 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokomizo,T. et al.: "Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor., BLT2"J.Biol.Chem.. 276. 12454-12459 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wu,C. et al.: "Evidence for the autocrine induction of capacitation of mammalian spematozoa"J.Biol.Chem.. 276. 26962-26968 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamashita,A. et al: "ATP-independent fatty acyl-CoAsynthesis from phospholipid : coenzyme A-dependent transacylation activity toward lysophosphatidic acid catalyzed by acyl-CoA : lysophosphatidic acid acyltransferase"J.Biol.Chem.. 276. 26745-26752 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Noiri,E. et al.: "An in vivo approach owing the chemotaclic activity of leukotriene B4 in acute renal ischemic-reperfusion injury"Proc.Natl.Acad.Sci.USA. 97. 823-828 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagase,T. et al.: "Acute lung injury by sepsis and acid aspiration : a key role for cylosolic phospholipase A2"Nature lmmunol.. 1. 42-26 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kato,K. et al.: "Cell-specific transcriptional regulation of human leukotriene B4 receptor gene"J.Exp.Med.. 192. 413-420 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokomizo,T. et al.: "A second leukotriene B4 receptor, BLT2. Anew therapeufic targen in inflammation and immunological discorders"J.Exp.Med.. 192. 421-432 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Asai, K.et al.: "Human Group IVC phospholipase A2 (cPLA2) : roles in the membrane remodeling and activation induced by oxidative stress"Journal of Biological Chemistry. 278. 8809-8814 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taniguchi, M.et al.: "Distorted odor map in the olfactory bulb of semaphoring 3A-deficient mice"Journal of Neurosciences. 23. 1390-1397 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagase, T.et al.: "A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis"Nature medicine. 8. 480-484 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ogasawara, H.et al.: "Characterization of mouse cysteinyl leukotriene receptors mCysLT1 and mCysLT2 : Differential pharamacological properties and tissue distribution"Journal of Biological Chemistry. 277. 18763-18768 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fukunaga, K.et al.: "Single nucleotide polymorphism of human platelet-activating factor receptor impairs G-protein activation"Journal of Biological Chemistry. 276. 43025-43030 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagase, T., et al.: "Acute lung injury by sepsis and acid aspiration : a key role for cytosolic phospholipase A2"Nature Immunology. 1. 42-46 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fukunaga, K, et al.: "SNP of human PAF receptor impairs G-protein activation"Journal of Biological Chemistry. 276. 43025-43030 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamashita, A, et al.: "ATP-independent fatty-acid Ce A synthesis from"Journal of Biological Chemistry. 276. 26745-26752 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wu, C. et al.: "Evidence for autocrine induction of capacitation of mamnalian spermatozoa"Journal of Biological Chemistry. 276. 12454-12459 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagase, T. et al.: "Acute lung injury by sepsis and acid aspiratin"Nature immunology. 1. 42-46 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ogasawara, H. et al.: "Characterization of mouse cysteinyl leukotries"Journal of Biological Chemistry. 277(in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ohshima, N. et al.: "Receptor-dependent metabolism of PAF in marine macrophages"Journal of Biological Chemistry. 277(in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Noiri,E.,Yokomzo,T.,Nakao,A. et al.: "An in vivo approach showing chemotactic activity of leukotriene B4 in acute renal ischemic-reperfusion injury"Proceeding of National Academy of Sciences, United States of America. 97(2). 823-828 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Katoh,K.,Yokomizo.T.,Izumi.T.,and Shimizu,T.: "Cell-specific transcriptional regulation of human leukotriene B4 receptor gene."Journal of Experimental Medicine. 192(3). 413-420 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yokomizo,T.,Kato,K.,Terawaki,K.,Izumi,T.,and Shimizu,T.: "A second leukotriene B4 receptor, BLT2 : a new therapeutic target in inflammation and immunological disorders"Journal of Experimental Medicine. 192(3). 421-431 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nagase.T.,Uozumi,N.,Ishii,S.,Kume,K.,Izumi,T.,and Shimizu,T.: "Acute lung injury by sepsis and acid aspiration : a key role for cytosolic phospholipase A2."Nature Immunology. 1(1). 42-46 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakatani,N.,Uozumi,N.,Kume,K.,Murakami,M.,Kudo,I.,Shimizu,T.: "Role of cytosolic phospholipase A2 in the production of lipid mediators and histamine release in mouse bone-marrow-derived mast cells."Biochemical Journal. 352. 311-317 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tabuchi,S.,Kume,K.,Aihara,M.,and Shimizu,T.: "Expression of lysophosphatidic acid receptor in rat astrocytes : mitogenic effect and expression of neurotropic genes."Neurochemical Research. 25(5). 573-582 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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