Prostaglandin D2 Receptor Function

前列腺素 D2 受体功能

• 批准号: 7209626
• 负责人: RICHARD M. BREYER
• 金额: $ 15.69万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209626
• 关键词: T lymphocyte; biological signal transduction; dendritic cells; disease /disorder etiology; disease /disorder model; eicosanoid metabolism; eicosanoids; experimental allergic encephalomyelitis; genetically modified animals; human tissue; immunocytochemistry; in situ hybridization; inflammation; laboratory mouse; microglia; multiple sclerosis; pharmacology; prostaglandin endoperoxide synthase; prostaglandin receptor; prostaglandins; protein structure function; toxicology; western blottings

Prostaglandin D2 (PGD2) is a cyclooxygenase (COX)-derived metabolite of arachidonic acid that modulates a wide range of inflammatory processes. Evidence suggests that PGD2 plays an important role in inflammation in the central nervous system and may be involved in the pathogenesis of multiple sclerosis. PGD2 levels are markedly increased in the cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients compared to CSF from other neurological diseases. PGD2 exerts its actions via two G-protein coupled receptors, the classical prostaglandin D2 receptor designated DP and the more recently described chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2 or "DP2"). Each of these receptors is activated by physiologically relevant concentrations of PGD2, but they are distinguished by several criteria, including their activation and blockade by a panel of synthetic ligands, their signal transduction pathways, and their respective tissue distribution. Biological responses to PGD2 are complex and our current understanding of the role of these two receptors in mediating the inflammatory response is incomplete. We hypothesize that activation of the DP receptor plays a critical role in the pathogenesis of MS in a mouse model, experimental autoimmune encephalomyelitis, and theorize that activation of the DP receptor is a critical mediator of the pro-inflammatory effects of PGD2 in MS. To investigate this, we will carry out the following specific aims. In Specific Aim 1, we will characterize a novel signal transduction pathway of PGD2 receptors. In Specific Aim 2, we will determine the role of PGD2 receptors in immune/inflammatory cell function. The PGD2-evoked effects on purified microglia, dendritic cells and T-cell populations will be examined. In Specific Aim 3, we will determine the role of PGD receptors in experimental autoimmune encephalomyelitis using receptor selective ligands and transgenic mouse models. In Specific Aim 4, we will examine the expression of COX, PGD synthase enzymes and PGD2 receptors in MS patients. Demonstration of a critical role for PGD2 receptor subtype(s) in the pathogenesis of MS will identify a novel therapeutic target.

前列腺素D2（PGD2）是一种衍生的花生四烯酸的环氧合酶（COX）的代谢产物，可调节 广泛的炎症过程。有证据表明PGD2在 中枢神经系统的炎症，可能参与多发性硬化症的发病机理。 多发性硬化症患者的脑脊液（CSF）的PGD2水平明显增加 与其他神经疾病的CSF相比。 PGD​​2通过两个G蛋白耦合发挥作用 受体，经典前列腺素D2受体指定的DP，最近描述了 在Th2细胞（CRTH2或“ DP2”）上表达的趋化受体同源分子。每个 受体被PGD2的生理相关浓度激活，但它们的区别是 几个标准，包括它们的激活和由一组合成配体的封锁，它们的信号 转导途径及其各自的组织分布。对PGD2的生物学反应很复杂 我们目前对这两种受体在介导炎症反应中作用的理解是 不完整。 我们假设DP受体的激活在小鼠中MS的发病机理中起关键作用 模型，实验性自身免疫性脑脊髓炎，理论认为DP受体的激活是一种 PGD​​2在MS中的促炎作用的关键介体。为了调查这一点，我们将执行 遵循特定目标。在特定目标1中，我们将表征PGD2的新型信号转导途径 受体。在特定目标2中，我们将确定PGD2受体在免疫/炎症细胞中的作用 功能。 PGD​​2诱发的对纯化的小胶质细胞，树突状细胞和T细胞种群的影响将是 检查。在特定的目标3中，我们将确定PGD受体在实验自身免疫中的作用 使用受体选择性配体和转基因小鼠模型的脑脊髓炎。在特定目标4中，我们将 检查MS患者中COX，PGD合酶酶和PGD2受体的表达。 PGD​​2受体亚型在MS发病机理中的关键作用的证明将确定新型 治疗靶标。