GENETIC ANALYSIS OF B3 ADRENERGIC RECEPTOR FUNCTION

B3 肾上腺素受体功能的遗传分析

• 批准号: 2150378
• 负责人: BRADFORD B LOWELL
• 金额: $ 23.27万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-30 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2150378
• 关键词: RNase protection assay; adenylate cyclase; adipocytes; beta adrenergic agent; beta adrenergic receptor; bioenergetics; biological signal transduction; brown fat; cold temperature; diet; eating; genetically modified animals; human genetic material tag; insulin; laboratory mouse; lipolysis; nutrition related tag; obesity; oxygen consumption; pancreatic islet function; protein isoforms; receptor binding; receptor expression; receptor sensitivity; thermogenesis

Obesity is a prevalent disorder that often leads to diabetes and cardiovascular disease. We have recently found that transgenic mice engineered to have brown fat deficiency become markedly obese, suggesting that brown fat protects against the development of obesity. We now seek to better understand the mechanisms by which brown fat is regulated, specifically the role of beta/3-adrenergic receptors (beta/3-ARs). The activity of brown fat is controlled predominantly by the sympathetic nervous system. Norepinephrine, released from sympathetic nerves, activates brown fat by binding to adrenergic receptors. Recently, brown fat has been found to possess a highly specialized beta-adrenergic receptor (beta-AR), termed the beta/3-AR. This receptor is the most abundant beta-AR in adipose tissue and is decreased by 70-98% in genetic models of obesity. Pharmaceutical companies have synthesized "atypical" beta-AR agonists which stimulate beta/3-ARs, and these compounds hold promise as anti-obesity, anti-diabetes agents. For these reasons, there is great interest in the beta/3-AR, and the drugs which stimulate it. However, the function of beta/3-ARs in normal physiology, and the mechanisms by which atypical beta-AR agonists produce their effects, are incompletely understood. To address these issues, a genetic analysis of beta/3-AR function has been undertaken. Using homologous recombination, we have generated mice which completely lack beta/3-ARs. These animals will be used to determine the function of beta/3-ARs in normal physiology and to define the receptor through which atypical beta-AR agonists produce their many effects. By reexpressing beta/3-ARs transgenically in selected tissues of deficient mice, it will be possible to establish the sites of action for these various effects. Finally, by transgenically reconstituting beta/3-AR deficient mice with human receptors, it will be possible to determine the capacity of activated human beta/3-ARs to augment thermogenesis. Given the high specificity of this genetic approach, information obtained from these mice concerning the function of this receptor, should be definitive in nature.

肥胖是一种普遍存在的疾病，通常会导致糖尿病和 心血管疾病。我们最近发现转基因小鼠 被设计成棕色脂肪缺乏的人会明显肥胖，这表明 棕色脂肪可以防止肥胖的发展。我们现在寻求 为了更好地理解棕色脂肪的调控机制， 特别是β/3-肾上腺素能受体(β/3-AR)的作用。 棕色脂肪的活动主要由交感神经控制。 神经系统。从交感神经释放出来的去甲肾上腺素， 通过与肾上腺素能受体结合来激活棕色脂肪。最近，布朗 脂肪已被发现具有高度专门化的β-肾上腺素能 受体(β-AR)，称为β/3-AR。这种受体是最多的 脂肪组织中丰富的β-AR，遗传性下降了70%-98% 肥胖症模型。制药公司已经合成了“非典型” 刺激β/3-AR的β-AR激动剂，这些化合物 有望成为抗肥胖、抗糖尿病的药物。出于这些原因，有 对β/3-AR和刺激它的药物非常感兴趣。 然而，β/3-ARs在正常生理中的作用，以及 非典型β-AR激动剂产生作用的机制是 不完全理解。 为了解决这些问题，已经对β/3-AR功能进行了遗传分析 承担了。利用同源重组，我们已经产生了 完全缺乏β/3-AR。这些动物将被用来确定 β/3-受体在正常生理中的作用及其受体的确定 非典型的β-AR激动剂通过它产生许多效应。通过 β/3-Ars在部分缺陷性组织中的转基因再表达 老鼠，将有可能建立这些行动的地点 各种效果。最后，通过转基因重组β/3-AR 有人类受体缺陷的小鼠，就有可能确定 激活的人β/3-ARs增强产热的能力。vt.给出 这种遗传方法的高度特异性，从以下方面获得的信息 这些小鼠关于这个受体的功能，应该是明确的 在自然界中。