权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

BRAIN ANGIOTENSIN RECEPTOR FUNCTION CONTROL AND ANATOMY

脑血管紧张素受体功能控制和解剖学

基本信息

批准号：
2264137
负责人：
Robert Charles Speth
金额：
$ 8.97万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-07-01 至 1995-09-29
项目状态：
已结题

项目摘要

This project will characterize brain angiotensin H (AII) receptor subtypes. The ultimate goals this project will be to determine the AII receptor subtypes mediating the various functions of AII in the brain. The rationale for these studies derives from recent observations that sulfhydryl reducing agents inhibit binding to one of the brain AII receptor subtypes. Since most studies of brain AII receptor binding have been done in the presence of sulfhydryl reducing agents, only one the of the brain AII receptor subtypes has been studied in detail. The specific aims of this project are to identify agents that act as selective agonists at brain AII receptor subtypes, to pharmacologically characterize the AII receptor subtypes, to determine if additional AII receptor subtypes occur in the brain, to determine the effects of sulfhydryl reactive agents on brain AII receptors, to determine if brain AII receptors couple to G proteins, and to examine functional responses to agonists and antagonists of AII administered directly into the brain. For functional studies, selective antagonists for one subtype will be given prior to the agonist to preclude mediation of the response by that subtype. Angiotensin II acts in the brain primarily to regulate fluid and electrolyte balance, however, it is also thought to have additional functions. The discovery of subtypes of AII receptors in the brain, may indicate that discrete, noncardiovascular functions for AII will be discovered. Since many brain diseases still have unknown etiologies, disturbances in brain angiotensinergic function could play a role in such disorders. The methods to be used in this project are peptide synthesis using FMOC techniques to prepare AII receptor subtype selective of analogs AII, radioligand binding assays, including in vitro receptor autoradiography to determine the AII receptor subtype profile of brain-nuclei. Binding assays will be done in the presence of ligands and conditions selective for individual AII receptor subtypes; and in vivo testing of responses, e.g., dipsogenesis and blood pressure changes, to angiotensins directly administered into the rat brain. The radioligand binding data will be analyzed by nonlinear regression procedures capable of determining and evaluating binding constants for multiple receptor subtypes. In vivo testing procedures will compare the efficacy of AT1, and AT2 receptor subtypes selective AII analogs in the absence and presence of All receptor selective antagonists by Students's t tests.

该项目将表征脑血管紧张素H（AII）受体亚型。该项目的最终目标是确定AII受体亚型介导AII在脑中的各种功能。的这些研究的理由来自最近的观察，巯基还原剂抑制与脑AII受体之一的结合亚型由于大多数关于脑AII受体结合的研究已经完成，在巯基还原剂的存在下，只有一个大脑 AII受体亚型已被详细研究。的具体目标这个项目是为了确定代理人作为选择性激动剂在大脑 AII受体亚型，用于表征AII受体亚型，以确定是否有其他AII受体亚型出现在脑，以确定巯基反应剂对脑AII的影响受体，以确定脑AII受体是否与G蛋白偶联，并检查对AII激动剂和拮抗剂的功能反应直接注入大脑。对于功能研究，选择性一种亚型的拮抗剂将在激动剂之前给予，由该子类型进行的响应的中介。血管紧张素II作用于大脑主要是调节液体和电解质平衡，然而，也被认为具有额外的功能。AII亚型的发现大脑中的受体，可能表明离散的，非心血管的所有的功能都将被发现。由于许多脑部疾病仍然有病因不明，脑血管紧张素能功能障碍可能在这些疾病中发挥作用。在本项目中使用的方法是使用FMOC技术进行肽合成以制备AII受体亚型类似物AII的选择性，放射性配体结合试验，包括体外受体放射自显影，以确定AII受体亚型谱脑核结合测定将在配体存在下进行，对单个AII受体亚型具有选择性的条件;以及测试响应，例如，致渴和血压变化，血管紧张素直接注入大鼠大脑。放射性配体结合数据将通过非线性回归程序进行分析，测定和评价多受体的结合常数亚型体内测试程序将比较AT 1的功效， AT 2受体亚型选择性AII类似物在不存在和存在下所有受体选择性拮抗剂均通过Students t检验。