Adrenergic and Purinergic Regulation of Target Cells

靶细胞的肾上腺素能和嘌呤能调节

• 批准号: 7116276
• 负责人: PAUL A INSEL
• 金额: $ 32.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116276
• 关键词: MDCK cell; adenosine triphosphate; adrenergic receptor; autocrine; biological signal transduction; genetically modified animals; hormone regulation /control mechanism; kidney cell; kidney function; laboratory mouse; nucleotide metabolism; nucleotides; paracrine; postganglionic fiber; protein structure function; purinergic receptor; receptor expression; renal tubule; stoichiometry

DESCRIPTION (provided by applicant): This application is a revised proposal to assess aspects of adrenergic receptor and P2Y purinergic receptor signalling. Our recent, preliminary data for this application include the identification and cloning of five different P2Y receptors in MDCK-D1 cells and discovery of a key role of ATP release as an autocrine/paracrine mechanism for establishing basal levels of signal transduction in these cells. The proposed studies will focus on studies in MDCK-D1 cells, designed to define information regarding nucleotide release and autocrine/paracrine signalling by P2Y-receptors, stoichiometry and compartmentation of G protein-coupled receptors/G protein and effector molecules, agonist-promoted regulation of adrenergic and P2-receptors, and in parallel studies using murine knockouts, the role of P2Y receptors and adrenergic receptors in regulation of renal function. The studies will test several hypotheses, including the possibilities that: 1) nucleotide release is a critical factor for the set point of multiple signal transduction pathways; 2) P2Y receptors, A1-AR and (B2-AR differentially target in polarized MDCK cells, and create compartmentalized signalling microdomains; and 3) adrenergic and P2Y receptors will show evidence of"cross regulation." The latter may contribute to modulation of response via sympathetic postganglionic neurons in the kidney and other cells. In additional experiments, we will attempt to define the functional activity of adrenergic and P2 receptors in vivo by the studies of mice with knockouts of certain receptors. Overall, the data should provide new insights into regulation of epithelial cells, in particular renal epithelial cells, by adrenergic and P2Y receptors and should help define the cell and renal physiological role of those receptors. In addition, the findings may have pathophysiologic and therapeutic implications for diseases such as cardiovascular, renal, and other disorders that involve the sympathetic nervous system or in which cell injury leads to release of nucleotides.

描述（由申请人提供）：本申请是评估肾上腺素能受体和P2Y嘌呤能受体信号传导方面的修订提案。 我们最近针对该应用的初步数据包括 MDCK-D1 细胞中五种不同 P2Y 受体的鉴定和克隆，以及发现 ATP 释放作为自分泌/旁分泌机制在这些细胞中建立信号转导基础水平的关键作用。 拟议的研究将集中于 MDCK-D1 细胞的研究，旨在定义有关 P2Y 受体的核苷酸释放和自分泌/旁分泌信号传导、G 蛋白偶联受体/G 蛋白和效应分子的化学计量和区划、激动剂促进的调节的信息肾上腺素能和 P2 受体的研究，以及使用小鼠基因敲除的平行研究，研究 P2Y 受体和肾上腺素能受体在肾功能调节中的作用。 这些研究将测试几个假设，包括以下可能性：1）核苷酸释放是多种信号转导途径设定点的关键因素； 2)P2Y受体、A1-AR和(B2-AR差异性地靶向极化的MDCK细胞，并产生区室化的信号微结构域；以及3)肾上腺素能和P2Y受体将显示“交叉调节”的证据。 后者可能有助于通过肾脏和其他细胞中的交感神经节后神经元调节反应。 在其他实验中，我们将尝试通过对敲除某些受体的小鼠进行研究来定义体内肾上腺素能和 P2 受体的功能活性。 总体而言，这些数据应为肾上腺素能和 P2Y 受体对上皮细胞（特别是肾上皮细胞）的调节提供新的见解，并应有助于确定这些受体的细胞和肾脏生理作用。 此外，这些发现可能对心血管、肾脏和其他涉及交感神经系统或细胞损伤导致核苷酸释放的疾病等疾病具有病理生理学和治疗意义。