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Roles and regulation of lipid mediators

脂质介质的作用和调节

基本信息

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

项目摘要

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，并产生一类脂质介质。它们在自我防卫和维持体内平衡中起着重要作用。在过去的三年里，我们进行了生化和遗传实验，得到的结果如下：研究结果发表在近50篇原创文章和6篇评论或书籍章节中。胞质磷脂酶A2及其相关分子的研究。cpla2 α-缺失小鼠突触可塑性和生殖功能受损。该酶还在炎症性骨吸收、自身免疫性关节炎、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，选择性cPLA2a抑制剂将对这些疾病有益。除了cPLA2的一个亚型外，我们还发现了该酶的β和γ亚型。β-亚型具有钙敏感的C2结构域，而g-亚型则被活性氧激活。我们还发现了一种新的截断的cPLA2亚型，通过刺激在齿状回中特异性表达。白三烯受体的表征。我们鉴定出4种不同类型的白三烯受体（BLT1、BLT2、CysLT1和CysLT2）。它们通过同源启动子激活在细胞和组织中表达不同。我们详细阐明了这些受体的信号转导，并建立了过表达或缺乏这些受体的细胞。更系统的表型分析将通过小鼠的基因靶向来完成。其他类型受体的表征。我们分析了PAF（血小板活化因子）受体，进一步发现PAF深入参与了小脑颗粒细胞的炎症反应、精子获能和神经元迁移。我们还确定了PAF的命运（其分解为溶血磷脂，并酰基化为1-烷基-磷脂）。通过SNP分析，我们在哮喘家族的细胞内第三结构域发现了一个新的突变。