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.

细胞刺激后，激活了各种类型的磷脂酶，并产生一类脂质介质。它们在自卫和维持体内平衡方面发挥了重要作用。在过去的三年中，我们进行了生化和遗传实验，并获得了如下的结果。结果已发表在近50篇原始文章和6个评论或书籍章节中。1。对胞质磷脂酶A2和相关分子的研究表明，突触可塑性和繁殖障碍。该酶在炎症性骨骼恢复，自身免疫性关节炎，急性呼吸窘迫综合征（ARDS）和博来霉素诱导的肺纤维化方面也起着重要作用。这是选择性CPLA2A抑制剂对这些疾病的有益。除了CPLA2的亚型外，我们还发现了酶的β和γ亚型。尽管β-亚型具有CA敏感的C2结构域，但G-Subtype被活性氧气激活。我们还发现了一种新型的CPLA2截短同工型，该同工型通过刺激在齿状回中表达。2。白细胞受体的表征。我们确定了4种不同类型的白细胞受体（BLT1，BLT2，CYSLT1和CYSLT2）。它们通过相关启动子激活在细胞和组织中的不同表达。我们阐明了这些受体的详细信号转导，并已建立的细胞过表达或缺乏这些受体。通过基因靶向小鼠，将进行更系统的表型分析3。对其他类型的受体的表征。我们分析了PAF（血小板激活因子）受体，并进一步发现PAF与小脑颗粒细胞中的炎症反应，精子的电容和神经元迁移深深涉及。我们还确定了PAF的命运（其对溶血脂的崩溃以及对1-烷基1-磷脂的反应）。通过SNP分析，我们在哮喘科中的第三个细胞内结构域中发现了一个新型突变。