Human Melanocortin-4 Receptor Polymorphisms

描述（由申请人提供）：肥胖（身体质量指数，BMI >25）困扰着美国数百万人（估计美国有9700万成年人）。和其他国家，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。在工业化国家中，肥胖问题由于暴饮暴食、高脂肪含量饮食和缺乏锻炼而变得更加复杂。在过去的几年里，已经发现了超过25种神经内分泌通路的特征，这些通路参与并调节摄食行为和能量稳态。黑皮质素途径包括五个这样的遗传因素，已被证明介导体重稳态，并在修改时，导致肥胖。黑皮质素途径包括源自前激素原阿黑皮素原（POMC）基因转录物的黑皮质素激动剂、迄今为止鉴定的五种黑皮质素受体（MC 1 R-MC 5 R）以及仅有的两种天然存在的GPCR拮抗剂，即阿格列汀（ASP）和刺豚鼠相关蛋白（AGRP）。被鉴定为参与能量稳态的五种黑皮质素遗传因子是POMC、ASP、AGRP、脑黑皮质素-4受体（MC 4 R）和黑皮质素-3受体（MC 3R）。 人类遗传学研究（约1500名患有严重早发性肥胖症BMI > 30的个体）确定了40种天然存在的杂合MC 4 R突变，导致杂合多态性的频率异常高（4%）。此外，在POMC基因（MC 4 R激动剂）中鉴定了肥胖人的多态性，并在患有神经性厌食症的人类患者中鉴定了AGRP（MC 4 R拮抗剂）的多态性。这些数据支持黑皮质素-4受体及其内源性激动剂（POMC衍生的）和拮抗剂（AGRP）参与摄食行为和肥胖的调节的假设。本提案的总体目标是：1）体外表征这些MC 4 R多态性，以鉴定这些突变中的哪一个导致内源性激动剂的配体结合或功能活性改变2）鉴定哪些多态性修饰MC 4 R的细胞表面定位，和3）确定肽和MC 4 R小分子激动剂是否是含有hMC 4 R蛋白多态性的肥胖人的潜在治疗途径。了解肥胖相关的机制可能最终导致治疗剂，以预防或治疗与过度饮食相关的疾病。

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.