KININ RECEPTORS--MOLECULAR PROPERTIES AND REGULATION

激肽受体——分子特性和调控

• 批准号: 2180990
• 负责人: Fredrik L.M. Leeb-Lundberg
• 金额: $ 18.72万
• 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 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2180990
• 关键词: G protein; biological signal transduction; bradykinin; hormone receptor; hormone regulation /control mechanism; inflammation; kallikreins; kinins; laboratory rabbit; laboratory rat; molecular cloning; phosphatidylinositols; phospholipase A2; phospholipase C; phosphorylation; protein purification; protein tyrosine kinase; receptor binding; receptor expression; tissue /cell culture; vasoactive agent

This grant is requested to support a program in basic research aimed at elucidation at the molecular level of the properties, mode of functioning, and mechanisms of regulation of receptors for vasoactive peptide hormones. Kinin peptides, of which bradykinin is an important example, are exquisitely potent vasoactive agonists and are released extracellularly instantaneously following tissue trauma and injury from high molecular weight prohormones, kininogens, through the action of specific proteases, kallikreins. The pharmacological action of kinins, which include vasodilatation, increased vascular permeability, smooth muscle contraction, pain, and cell proliferation, and the mechanism of kinin release indicate that these peptides serve important roles in a number of pathophysiological and physiological processes such as inflammation and blood pressure regulation. In order to understand the normal and abnormal control of these important processes, it is absolutely crucial to understand at the molecular level the functional and structural characteristics of kinin receptors. To this end, we have developed a comprehensive research plan with four intimately linked major goals: 1) To understand the nature of the binding of kinin agonists and antagonists to kinin receptors. This goal may ultimately lead to the development of new routes of manipulating these receptors in vivo. 2) To understand how agonist binding to kinin receptors translates into a stimulation of various intracellular effector enzymes including phospholipases and tyrosine and serine/threonine protein kinases. 3) To understand the cellular mechanisms underlying regulation of kinin receptors which includes receptor internalization and possibly also receptor phosphorylation. 4) To understand the structural basis of kinin receptor function by studying the biochemical properties of kinin receptors through receptor purification and receptor cDNA cloning. The results obtained from this multi-faceted research program will increase our knowledge of the mechanisms involved in kinin actions and should further enhance our understanding of pathologies in which kinins serve a role such as acute and chronic inflammation and hypertension. Our results should also be of general importance in understanding regulation of the vasculature and cell growth since the cellular signaling pathways used by kinins are common to several other vasoactive and mitogenic agonists.

这项拨款是为了支持一项基础研究计划， 在分子水平上阐明了这些性质、模式 血管活性物质受体的功能和调节机制 肽激素 激肽肽，其中缓激肽是一种重要的 例如，是非常有效的血管活性激动剂， 在组织创伤和损伤后立即发生细胞外 高分子量激素原，激肽原，通过作用， 特定的蛋白酶，激肽释放酶。 激肽的药理作用， 包括血管扩张， 血管通透性，平滑 肌肉收缩、疼痛和细胞增殖，以及 激肽释放表明，这些肽在 许多病理生理和生理过程，如 炎症和血压调节。 为了解 这些重要过程的正常和异常控制， 在分子水平上理解功能性的 和激肽受体的结构特征。 为此我们 制定了一项全面的研究计划，其中包括四个密切相关的主要领域， 目的：1）了解激肽激动剂与受体结合的性质， 激肽受体的拮抗剂。 这一目标可能最终导致 开发在体内操纵这些受体的新途径。 （二） 为了了解激动剂如何与激肽受体结合， 刺激各种细胞内效应酶，包括 磷脂酶以及酪氨酸和丝氨酸/苏氨酸蛋白激酶。 3)到 了解激肽调节的细胞机制 受体，包括受体内化，也可能 受体磷酸化 4)了解激肽的结构基础 通过研究激肽的生物化学特性， 通过受体纯化和受体cDNA克隆来获得受体。 的 从这个多方面的研究计划中获得的成果将增加 我们对激肽作用机制的了解， 进一步加深我们对激肽发挥作用的病理学的理解 作用如急慢性炎症和高血压。 我们 结果在理解监管方面也具有普遍重要性 血管和细胞生长，因为细胞信号通路 激肽与其他几种血管活性和促有丝分裂的 激动剂