BETA 1 AND BETA 3 ADRENORECEPTORS

Beta 1 和 Beta 3 肾上腺素受体

基本信息

批准号：
6380782
负责人：
James G Granneman
金额：
$ 24.65万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-01 至 2004-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6380782
关键词：
adenylate cyclase adipocytes animal genetic material tag beta adrenergic agent beta adrenergic receptor biological signal transduction chimeric proteins connective tissue pharmacology enzyme activity gene mutation laboratory rat mitogen activated protein kinase protein structure function receptor binding receptor expression recombinant proteins tissue /cell culture

项目摘要

The beta3 adrenergic receptor (AR) has been proposed to be a therapeutic target for the treatment of obesity and adult-onset diabetes, and recent work has identified a polymorphism in the human beta3-AR gene that is associated with excess weight gain and insulin resistance. Beta3-AR are expressed almost exclusively in adipocytes where they are co-expressed with beta1-AR. The tissue-specific pattern of beta3-AR gene expression and its co-existence in adipose tissue with beta1-AR has raised several fundamental questions. First, the coexpression of beta1-and beta3-AR in fat cells implies that the beta3-AR subtypes serve different signaling functions in adipocytes, and recent evidence indicates that beta1- and beta3-AR have unique signaling properties and that these receptors activate distinct pathways in adipocytes. The organization of beta1- and beta3-AR signaling in adipocytes will be further characterized and specific hypotheses regarding the biochemical and cellular basis of that organization will be tested. Second, beta1- and beta3-AR exhibit several unique pharmacological and biochemical properties that are amenable to molecular analysis. A panel of epitope- tagged, mutated and chimeric receptors have been created that will allow validation of observations made in adipocyte and further dissection of the molecular bases of beta3-AR subtype-specific signaling properties. These analyses will include examination of the molecular pharmacology of aryloxypropranolamine and phenethanolamine agonists, compounds being developed as selective beta3-AR agonists. An understanding of how these compounds differentially interact with the beta 3-AR subtypes, and the impact of that interaction on receptor signaling is key to understanding their biological actions. Specific aims are: Aim 1. To investigate the biochemical organization of beta3-AR signaling in adipocytes. Aim 2. To further characterize the differential signaling properties of beta1- beta3-AR and to examine the cellular and molecular basis. Specific Aim 3. To examine the molecular pharmacology of beta3-AR-selective agonists.

β3肾上腺素能受体（AR）已被认为是一种治疗性治疗肥胖和成人糖尿病的靶标工作已经确定了人beta3-ar基因中的多态性与体重增加过多和胰岛素抵抗有关。 beta3-ar是几乎完全在共表达的脂肪细胞中表达与beta1-ar。 beta3-ar基因表达的组织特异性模式它与beta1-ar中的脂肪组织共存已增加了几个基本问题。首先，beta1和beta3-ar的共表达在脂肪细胞中意味着beta3-ar亚型服务不同脂肪细胞中的信号传导功能，最近的证据表明 beta1-和beta3-ar具有独特的信号传导属性，并且受体在脂肪细胞中激活不同的途径。组织脂肪细胞中的beta1-和beta3-ar信号传导将进一步关于生化和该组织的蜂窝基础将进行测试。第二，beta1-和 Beta3-ar展示了几种独特的药理和生化适合分子分析的特性。一个表位置 - 已经创建了标记，突变和嵌合受体验证脂肪细胞中进行的观察结果和进一步解剖 beta3-ar亚型特异性信号传导特性的分子碱基。这些分析将包括检查分子药理学芳氧甲氧甲醇胺和苯乙烯胺激动剂，化合物是发展为选择性beta3-ar激动剂。对这些方式的理解化合物与Beta 3-AR亚型的差异相互作用，并且该相互作用对受体信号的影响是理解的关键他们的生物行为。具体目的是：目标1。调查脂肪细胞中β3AR信号传导的生化组织。目标2。为了进一步表征beta1-的差异信号传导特性 beta3-ar并检查细胞和分子基础。具体目标 3。检查β3-AR选择性激动剂的分子药理学。