| Project/Area Number |
12308034
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | The University of Tokyo |
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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)
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| 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)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| 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)
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| Keywords | Lipid 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 |
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| 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.
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