Human Melanocortin-4 Receptor Polymorphisms

描述(申请人提供)：肥胖(身体质量指数，BMI&GT；25)在美国困扰着数百万人(美国估计有9700万成年人)。并且是心脏病、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加剧。在过去的几年里，已经发现了超过25条神经内分泌途径，它们参与并调节摄食行为和能量平衡。黑素皮质素途径包括五个这样的遗传因素，已被证明调节体重动态平衡，当被修改时，导致肥胖。黑素皮质素途径包括来源于前阿片黑素皮质素(POMC)基因转录本的黑素皮质素激动剂、迄今已发现的5种黑素皮质素受体(MC1R-MC5R)，以及仅有的两种天然存在的GPCRs拮抗剂：刺鼠(ASP)和刺鼠相关蛋白(AGRP)。参与能量平衡的5个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)。 对人类的遗传学研究(约1500名患有严重早发性肥胖症的人)发现了40个自然发生的MC4R杂合性突变，导致杂合性多态的频率异常高(4%)。此外，肥胖者的POMC基因(MC4R激动剂)和AGRP(MC4R拮抗剂)的多态也在神经性厌食症患者中被发现。这些数据支持黑素皮质素-4受体及其内源性激动剂(POMC衍生)和拮抗剂(AGRP)参与调节摄食行为和肥胖的假说。这项建议的总体目标是1)在体外表征这些MC4R多态，以确定这些突变中的哪一个会导致内源性激动剂(POMC衍生多肽)或拮抗剂(AGRP)的配基结合或功能活性改变，确定哪些多态改变MC4R的细胞表面定位，以及3)确定多肽和MC4R小分子激动剂是否为含有hMC4R蛋白多态的肥胖者的潜在治疗途径。了解肥胖相关机制可能最终导致治疗药物来预防或治疗与过量饮食相关的疾病。

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.