Human Melanocortin-4 Receptor Polymorphisms

描述（由申请人提供）：肥胖（身体质量指数，BMI bbbb25）在美国和其他国家折磨着数百万人（美国估计有9700万成年人），是心脏病、II型糖尿病、中风、高血压和发病率的主要危险因素。在工业化国家，肥胖问题因暴饮暴食、高脂肪饮食和缺乏锻炼而更加严重。在过去的几年里，已经发现了超过25种神经内分泌途径的特征，这些途径已被确定参与和调节摄食行为和能量稳态。黑素皮质素通路包括五种遗传因子，这些遗传因子已被证明可以调节体重稳态，当它们被改变时，就会导致肥胖。黑素皮质素通路包括黑素皮质素激动剂，源自激素前原原原黑素皮质素（POMC）基因转录物，迄今已鉴定的五种黑素皮质素受体（MC1R-MC5R），以及仅有的两种天然存在的gpcr拮抗剂，针刺子（ASP）和针刺子相关蛋白（AGRP）。已确定参与能量稳态的五种黑素皮质素遗传因子是POMC、ASP、AGRP、脑黑素皮质素-4受体（MC4R）和黑素皮质素-3受体（MC3R）。

DESCRIPTION (provided by applicant): Obesity (body mass index, BMI >25) afflicts millions of people in the United States (an estimated 97 million adults in the U.S.) and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke, hypertension, and morbidity. In industrialized countries, the problem of obesity is compounded by overeating, a high fat content diet, and a lack of exercise. The last few years have seen the characterization of over 25 neuroendocrine pathways that have been identified to participate in and regulate feeding behavior and energy homeostasis. The melanocortin pathway includes five such genetic factors that have been demonstrated to mediate weight homeostasis, and when modified, result in obesity. The melanocortin pathway includes the melanocortin agonists, derived from the preprohormone proopiomelanocortin (POMC) gene transcript, the five melanocortin receptors identified to date (MC1R-MC5R), and the only 2 naturally occurring antagonists of GPCRs, agouti (ASP) and agouti-related protein (AGRP). The five melanocortin genetic factors identified as being involved in energy homeostasis are POMC, ASP, AGRP, the brain melanocortin-4 receptor (MC4R), and the melanocortin-3 receptor (MC3R). Genetic studies in humans (ca 1500 individuals with severe early-onset obesity BMI > 30) identified 40 naturally occurring heterozygous MC4R mutations, resulting in an unusually high frequency (4%) of heterozygous polymorphisms. Additionally, polymorphisms of obese humans were identified in the POMC gene (MC4R agonists), and polymorphisms of the AGRP (MC4R antagonist) were identified in human patients with Anorexia Nervosa. These data support the hypothesis that the melanocortin-4 receptor and its endogenous agonists (POMC derived) and antagonist (AGRP) are involved in the regulation of feeding behavior and obesity. The overall objectives of this proposal are to 1) characterize these MC4R polymorphisms in vitro to identify which of these mutations results in altered ligand binding or functional activity of either the endogenous agonist (POMC derived peptides) or antagonist (AGRP) 2) identify which polymorphisms modify cell surface localization of the MC4R, and 3) determine if peptides and MC4R small molecule agonists are potential therapeutic avenues for obese humans containing hMC4R protein polymorphisms. Understanding obesity related mechanisms may ultimately result in therapeutic agents to prevent or treat the diseases associated with over eating.