BETA 1 AND BETA 3 ADRENORECEPTORS

Beta 1 和 Beta 3 肾上腺素受体

• 批准号: 2689285
• 负责人: James G Granneman
• 金额: $ 13.35万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2689285
• 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

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。