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（PGD 2）是花生四烯酸的环氧合酶（考克斯）衍生的代谢物，其调节 一系列的炎症过程有证据表明，PGD 2在 在中枢神经系统炎症，并可能参与多发性硬化症的发病机制。 多发性硬化（MS）患者脑脊液（CSF）中PGD 2水平显著升高 与其他神经系统疾病的脑脊液相比。PGD 2通过两个G蛋白偶联发挥作用， 受体，经典的前列腺素D2受体指定DP和最近描述的 Th 2细胞上表达的化学引诱物受体同源分子（CRTH 2或“DP 2”）。这一切成功都 受体被生理相关浓度的PGD 2激活，但它们的区别在于 几个标准，包括它们被一组合成配体激活和阻断，它们的信号 转导途径以及它们各自的组织分布。对PGD 2的生物学反应是复杂的 我们目前对这两种受体在介导炎症反应中的作用的理解是， 不完整 我们假设DP受体的激活在小鼠MS的发病机制中起着关键作用 模型，实验性自身免疫性脑脊髓炎，并从理论上说，DP受体的激活是一个 在MS中PGD 2促炎作用的关键介质。为了研究这一点，我们将进行 具体目标。在具体目标1中，我们将描述PGD 2的一种新的信号转导途径 受体。在具体目标2中，我们将确定PGD 2受体在免疫/炎症细胞中的作用。 功能PGD 2对纯化的小胶质细胞、树突状细胞和T细胞群的诱发作用将被研究。 考察在具体目标3中，我们将确定PGD受体在实验性自身免疫性疾病中的作用。 使用受体选择性配体和转基因小鼠模型的脑脊髓炎。在具体目标4中，我们 检测MS患者中考克斯、PGD合成酶和PGD 2受体的表达。 证明PGD 2受体亚型在MS发病机制中的关键作用将确定一种新的 治疗靶点