Transgenic analysis of CNS melanocortin receptors

CNS 黑皮质素受体的转基因分析

• 批准号: 6473178
• 负责人: ROBERT A KESTERSON
• 金额: $ 35.52万
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6473178
• 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：（由申请人提供）肥胖是最常见的营养问题 美国的疾病以及成年人的寿命缩短 与肥胖相关的可归因于 II 型的发展 糖尿病以及心血管疾病，包括中风， 高血压和心脏病。 Advances in our understanding of underlying 可能导致能量失衡的机制已得到以下研究的帮助 重点关注脂肪细胞和大脑。最近发现颠覆 中枢神经系统中黑皮质素信号传导的异常是黄种人肥胖的原因 肥胖小鼠已经验证了存在于肥胖小鼠中的类似途径 人类，以及黑皮质素 4 突变的鉴定 受体（MC4-R）和阿片黑皮素原（POMC）基因导致人类疾病。在 CNS 中，表达黑皮质素受体（MC4-R 和/或 MC3-R）的神经元是 由起源于的单独且独立的神经元群体调节 下丘脑弓形核 (ARC)，表达以下任一信号的前体： 黑皮质素激动剂 (POMC) 或天然存在的拮抗剂 （agouti 相关蛋白或 AGRP）。 POMC 和 AGRP 神经元均表达受体 对于瘦素。 MC4-R 缺陷动物重现刺豚鼠引起的肥胖 综合征，但人们对与该综合征相关的神经内分泌回路知之甚少 黑皮质素通过该受体控制能量平衡。自从 黑皮质素受体在整个中枢神经系统中表达，其直接目标是 这个项目是为了检验下丘脑而不是下丘脑的总体假设 MC4-R 的脑干表达控制黑皮质素对能量平衡的控制， 以及下丘脑中MC4-R表达的具体假设 促甲状腺素释放激素 (TRH) 和黑色素浓缩激素 (MCH) 正常体重稳态需要神经元。最佳条件 使用腺病毒调节成年小鼠中枢神经系统转基因表达 cre/lox技术也将被建立。然而，长期目标是 该提案是开发动物模型来定义神经回路 其中 a-MSH、AGRP 和 CNS 黑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 表达在 CNS 将使用 cre 重组酶进行调节。