Transgenic analysis of CNS melanocortin receptors

描述：（由申请人提供）肥胖是最常见的营养 在美国，疾病和成年人，寿命缩短， 与肥胖相关的疾病可归因于II型糖尿病的发展。 糖尿病以及心血管疾病包括中风， 高血压和心脏病。我们对潜在的 可能导致能量失衡的机制已经得到了研究的帮助， 关注脂肪细胞和大脑。最近发现， 中枢神经系统中的黑皮质素信号是黄色肥胖的原因 肥胖小鼠导致验证了存在于 人类，以及黑皮质素4突变的鉴定 受体（MC 4-R）和阿黑皮素原（POMC）基因引起人类疾病。在 CNS，表达黑皮质素受体（MC 4-R和/或MC 3-R）的神经元， 由起源于大脑皮层的独立的神经元群体调节。 下丘脑弓状核（ARC），表达以下两种神经元的前体： 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 瘦素虽然MC 4-R缺陷动物重演了刺豚鼠诱导的肥胖， 综合征，很少有人知道有关的神经内分泌回路， 黑皮质素通过这种受体控制能量平衡。以来 黑皮质素受体在整个CNS中表达， 这个项目是为了测试下丘脑和非下丘脑的整体假设， MC 4-R的脑干表达支配黑皮质素对能量平衡的控制， 下丘脑MC 4-R表达的特异性假说 促甲状腺素释放激素（TRH）和黑色素浓集激素（MCH） 神经元是正常体重稳态所必需的。最优条件 使用腺病毒调节成年小鼠的CNS转基因表达， 还将建立cre/lox技术。然而，长期目标是 这项建议是开发动物模型来定义神经回路， 其中α-MSH、AGRP和CNS黑皮质素受体调节进食行为， 产热和心血管控制。为此，MC 4-R表达在 将使用cre重组酶调节CNS。

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.