Transgenic analysis of CNS melanocortin receptors

CNS 黑皮质素受体的转基因分析

• 批准号: 6837819
• 负责人: ROBERT A KESTERSON
• 金额: $ 0.23万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837819
• 关键词: bioenergetics; biological signal transduction; central nervous system; disease /disorder proneness /risk; gene expression; gene targeting; genetic recombination; genetic regulation; genetically modified animals; hypothalamus; laboratory mouse; leptin; molecular genetics; neurons; neuropeptide receptor; neurophysiology; obesity; proopiomelanocortin; receptor expression; recombinase; thyrotropin releasing hormone; transfection

DESCRIPTION: (provided by applicant) Obesity is the most common nutritional disorder in the United States and, in adults, the reduction in lifespan associated with obesity can be attributed to the development of Type II diabetes mellitus as well as cardiovascular disorders including stroke, hypertension and heart disease. Advances in our understanding of underlying mechanisms that can cause energy imbalances have been aided by studies that focus on both the adipocyte and the brain. The recent discovery that disruption of melanocortin signaling in the CNS is the cause of obesity in the yellow obese mouse has led to the verification of a similar pathway that exists in humans, as well as the identification of mutations in the melanocortin 4 receptor (MC4-R) and proopiomelanocortin (POMC) genes causing human disease. In the CNS, neurons that express melanocortin receptors (MC4-R and/or MC3-R) are regulated by separate and independent populations of neurons originating in the arcuate nucleus of the hypothalamus (ARC), which express precursors for either a melanocortin agonist (POMC) or a naturally occurring antagonist (agouti-related protein or AGRP). Both POMC and AGRP neurons express receptors for leptin. While MC4-R deficient animals recapitulate agouti-induced obesity syndrome, little is known about the neuroendocrine circuits involved with melanocortin control of energy balance through this receptor. Since melanocortin receptors are expressed throughout the CNS, the immediate goals of this project are to test the overall hypothesis that hypothalamic and not brainstem expression of MC4-R governs melanocortin control of energy balance, and the specific hypotheses that expression of MC4-R in hypothalamic thyrotropin-releasing hormone (TRH) and melanin-concentrating hormone (MCH) neurons is required for normal weight homeostasis. Conditions for optimal regulation of CNS transgene expression in adult mice using an adenovirus and cre/lox technology will also be established. However, the long-term goal of this proposal is to develop animal models to define the neural circuitry by which a-MSH, AGRP, and CNS melanocortin receptors regulate feeding behaviour, thermogenesis, and cardiovascular control. To this end, MC4-R expression in the CNS will be modulated using cre recombinase.

描述：(申请人提供)肥胖是最常见的营养因素 美国的疾病和成年人寿命的减少 与肥胖有关的疾病可归因于II型的发展 糖尿病以及包括中风在内的心血管疾病， 高血压和心脏病。我们对潜在因素的理解的进展 可能导致能量失衡的机制得到了研究的帮助， 同时关注脂肪细胞和大脑。最近的发现，这一颠覆 中枢神经系统中黑素皮质素信号的变化是导致黄色皮肤肥胖的原因 肥胖的小鼠导致了对存在于 人类，以及黑素皮质素4基因突变的鉴定 受体(MC4-R)和前阿片黑素皮质素(POMC)基因导致人类疾病。在……里面 表达黑素皮质素受体(MC4-R和/或MC3-R)的中枢神经系统神经元 由独立和独立的神经元群体调控，这些神经元起源于 下丘脑弓状核(ARC)，它表达以下任一种的前体 黑素皮质素激动剂(POMC)或自然产生的拮抗剂 (刺鼠相关蛋白或AGRP)。POMC和AGRP神经元均表达受体 瘦素。而MC4-R缺陷的动物则重述了刺鼠诱导的肥胖 综合征，对参与其中的神经内分泌回路知之甚少 黑素皮质素通过该受体控制能量平衡。自.以来 黑素皮质素受体在整个中枢神经系统都有表达，其直接目标是 这个项目是为了检验下丘脑和非丘脑的总体假设 脑干MC4-R的表达控制着黑素皮质素对能量平衡的控制， 并提出MC4-R在下丘脑表达的具体假设 促甲状腺激素释放激素(TRH)和黑色素浓缩激素(MCH) 正常体重的动态平衡需要神经元。最优的条件 重组腺病毒对成年小鼠中枢神经系统转基因表达的调节 还将建立CRE/LOX技术。然而，长期目标是 这个建议是开发动物模型来定义神经回路，方法是 α-MSH、AGRP和CNS黑素皮质素受体调节摄食行为， 生热作用和心血管控制。为此，MC4-R在 CNS将使用cre重组酶进行调制。