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2002 Fiscal Year Final Research Report Summary

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
KeywordsLipid mediators / arachidonic acid / lung fibrosis / inflammation / leukotrienes / phospholipase A2 / allegy / PAF
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.

  • Research Products

    (22 results)

All Other

All Publications (22 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
  • [Publications] Kato, K.et al.: "Cell-specific transcriptional regulation of human leukotriene B4 receptor gene"Journal of Experimental Medicine. 192. 413-420 (2000)

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

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      「研究成果報告書概要(和文)」より
  • [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
  • [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
  • [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)

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

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      「研究成果報告書概要(欧文)」より
  • [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)

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      「研究成果報告書概要(欧文)」より
  • [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)

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

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

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

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

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

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  • [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)

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      「研究成果報告書概要(欧文)」より
  • [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
  • [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
  • [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
  • [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

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Published: 2004-04-14  

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