KININ RECEPTORS--MOLECULAR PROPERTIES AND REGULATION

激肽受体——分子特性和调控

• 批准号: 6180462
• 负责人: Fredrik L.M. Leeb-Lundberg
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6180462
• 关键词: G protein; autocrine; biological signal transduction; bradykinin; caveolas; cytokine; fluorescence microscopy; genetic promoter element; hormone receptor; hormone regulation /control mechanism; inflammation; kinins; laboratory rabbit; receptor binding; receptor coupling; receptor expression; receptor sensitivity; tissue /cell culture; vascular smooth muscle

DESCRIPTION (Adapated from Investigator's Abstract): This grant is requested to support an ongoing program in basic research aimed at understanding the structural basis and molecular mechanisms underlying the function and regulation of receptors for vasoactive peptides. For this purpose, the P.I. will use the kinin receptor system as a model. Kinins, pro-inflammatory peptides released extracellularly following injury, act through two distinct receptors, B1 and B2, which both belong to the seven transmembrane-domain, G-protein-coupled receptor (GPCR) superfamily. The B2 receptor mediates the actions of bradykinin (BK), whereas the B1 receptor mediates the actions of the carboxypeptidase product des-Arg9BK. The physiological responses to kinins include vasodilatation, smooth muscle spasm, edema, hyperalgesia, pain, modulation of hormone and cytokine release, increased epithelial transport, and cell proliferation. Based on these properties, kinins have been implicated in a number of pathophysiological processes involving injury, inflammation, and healing. In order to understand regulation of peptide action in health and disease, a comprehensive research program with two intimately linked goals focusing on kinin receptors has been developed: 1) to study mechanisms of short-term regulation of B1 and B2 receptors by receptor agonists including desensitization and internalization, and 2) to study mechanisms of long-term regulation of B1 and B2 receptor expression by autocrine mechanisms through receptor agonists and by other factors involved in injury and inflammation. The combined study of B1 and B2 receptors also offers unique opportunities to identify structural requirements in peptide GPCR as the ligands and effectors for these receptors are similar while the receptors themselves show relatively little sequence homology. The goals of the research program will be achieved using established techniques from several disciplines including molecular biology, protein chemistry, and cellular imaging of fluoroprobes. This research program will increase our understanding of the regulation of kinin action in pathophysiological states such as inflammation, and will in turn, provide significant insights into general mechanisms of action and regulation of vasoactive peptides.

描述(改编自《调查者摘要》)：这笔拨款是 要求支持一项正在进行的基础研究方案，目的是 了解潜在的结构基础和分子机制 血管活性多肽受体的功能和调节。为了这个 目的：P.I.将使用激动素受体系统作为模型。金宁， 促炎性多肽在损伤后细胞外释放，ACT 通过两个不同的受体B1和B2，这两个受体都属于七种 跨膜区，G蛋白偶联受体(GPCR)超家族。B2 受体介导缓激肽(BK)的作用，而B1受体 介导羧肽酶产物DES-Arg9BK的作用。这个 对激动素的生理反应包括血管扩张、平滑肌 痉挛、水肿、痛觉过敏、疼痛、激素和细胞因子的调节 释放，增加上皮运输和细胞增殖。基于 这些特性，激动素已经被牵连到许多 包括损伤、炎症和愈合在内的病理生理过程。 为了了解多肽在健康和疾病中的作用调节，a 全面的研究计划，有两个密切相关的目标，重点是 激动素受体已被开发：1)研究短时程增强的机制 受体激动剂对B1和B2受体的调节作用 脱敏和内化；2)研究长效机制。 通过自分泌机制调节B1和B2受体的表达 受体激动剂和其他参与损伤和炎症的因素。 对B1和B2受体的联合研究也提供了独特的机会 确定多肽gpr中的结构要求作为配体和 这些受体的效应器是相似的，而受体本身 显示出相对较少的序列同源性。研究计划的目标 将使用来自几个学科的既定技术来实现 包括分子生物学、蛋白质化学和细胞成像 荧光探头。这项研究计划将增加我们对 激肽在以下病理生理状态中的作用调节 炎症，并将反过来提供对一般情况的重要洞察 血管活性多肽的作用机制和调节。