KININ RECEPTORS--MOLECULAR PROPERTIES AND REGULATION

这笔拨款是为了支持一个基础研究项目，目的是 在分子水平上阐明其性质、模式 血管活性受体的功能及其调节机制 多肽激素。激肽，其中缓激肽是一个重要的 例如，是非常有效的血管活性激动剂，并被释放 组织创伤和损伤后即刻细胞外 大分子前激素，激肽原，通过作用于 特定的蛋白酶，激肽释放酶。激动素的药理作用， 包括血管扩张，血管通透性增加，光滑 肌肉收缩、疼痛和细胞增殖，以及 激动素的释放表明这些多肽在 病理生理和生理过程的数量，如 炎症和血压调节。为了更好地理解 对这些重要过程的正常和异常控制，它是 对于在分子水平上理解功能 激动素受体的结构特征。为此，我们有 制定了一项全面的研究计划，其中包括四个密切相关的专业 目标：1)了解激动素激动剂和激动素结合的性质 激动素受体的拮抗剂。这一目标最终可能导致 开发在体内操纵这些受体的新途径。2) 为了了解激动剂与激动素受体结合是如何转化为 刺激各种细胞内效应酶，包括 磷脂酶、酪氨酸和丝氨酸/苏氨酸蛋白激酶。3)至 了解激动素调节的细胞机制 受体，包括受体内化，可能还有 受体磷酸化。4)了解激动素的结构基础 激动素的生化特性及其受体功能的研究 受体的纯化和受体基因的克隆。这个 从这个多方面的研究计划中获得的结果将会增加 我们对激动素作用机制的了解，应该 进一步加深我们对激肽在其中发挥作用的病理学的理解 一个角色，如急性和慢性炎症和高血压。我们的 结果对于理解监管也应该具有普遍的重要性 自细胞信号通路以来的血管系统和细胞生长 由激动素使用，是其他几种血管活性和有丝分裂原共同使用的 激动剂。

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.