Roles and regulation of lipid mediators

脂质介质的作用和调节

• 批准号: 12308034
• 负责人: SHIMIZU Takao
• 金额: $ 24.87万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12308034/
• 关键词: 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

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.

细胞受到刺激后，各种类型的磷脂酶被激活，产生一类脂质介质，它们在自我防御和维持体内平衡方面发挥着重要作用。在过去的三年里，我们进行了生化和遗传实验，并获得了这些结果。结果如下： 近50篇原创文章和6篇评论或书籍章节已发表。1．关于胞质磷脂酶A2和相关分子的研究。cPLA2α缺失小鼠表现出突触损伤。该酶还在炎症性骨吸收、自身免疫、关节炎急性呼吸窘迫综合征 (ARDS) 和博莱霉素诱导的肺纤维化中发挥重要作用，因此，除了一种亚型外，选择性 cPLA2a 抑制剂也有益于治疗这些疾病。在cPLA2中，我们还发现了该酶的β和γ亚型，而β亚型具有Ca敏感性C2结构域，而g亚型则被活性氧激活。 cPLA2 的截短异构体，通过刺激在齿状回中特异性表达。2.白三烯受体的表征。我们鉴定了 4 种不同类型的白三烯受体（BLT1、BLT2、CysLT1 和 CysLT2），它们在细胞和组织中表达不同。我们阐明了这些受体的详细信号转导，并建立了过度表达或缺乏这些受体的细胞。 3．其他类型受体的表征。我们分析了PAF（血小板激活因子）受体，进一步发现PAF与炎症反应、获能能力密切相关。我们还通过 SNP 嵌套确定了 PAF 的命运（其分解为溶血磷脂，并再酰化为 1-烷基1-磷脂）​​。在哮喘家族的第三个细胞内结构域中发现了一个新的突变。

项目成果

Yokomizo, T.et al.: "A second leukotriene B4 receptor, BLT2. A therapeutic target in inflammation"Journal of Experimental Medicine. 192. 421-432 (2000)

Yokomizo, T.等人：“第二种白三烯 B4 受体，BLT2。炎症的治疗靶点”实验医学杂志。

Ogasawara,H. et al.: "Characterization of mouse cysteinyl leukotriene receptor, mCysLt1 and mCysLT2"J.Biol.Chem.. 277. 18763-18768 (2002)

小笠原，H.

Nagase, T. et al.: "Acute lung injury by sepsis and acid aspiratin"Nature immunology. 1. 42-46 (2000)

Nagase, T. 等人：“败血症和酸性阿司匹丁引起的急性肺损伤”自然免疫学。

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)

Yokomizo,T.、Kato,K.、Terawaki,K.、Izumi,T. 和 Shimizu,T.：“第二种白三烯 B4 受体 BLT2：炎症和免疫性疾病的新治疗靶点”实验医学杂志。

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)

Miyaura 等人：“细胞质磷脂酶 A2α 在与炎症相关的前列腺素 E2 介导的骨吸收中的重要作用”J.Exp.Med.. 197. 1303-1310 (2003)