Defensins as Melanocortin Ligands

描述(申请人提供)：肥胖困扰着数百万人，是II型糖尿病和发病率的主要风险因素。黑素皮质素途径在小鼠和人类中已被明确识别，参与肥胖和能量平衡的调节。已被确认参与能量稳态的五个黑素皮质素遗传因素(前阿片黑素皮质素激动剂、Agti和Agti相关蛋白拮抗剂，以及黑素皮质素-4受体和黑素皮质素-3受体蛋白)。2007年，内源性β-防御素多肽被报道参与黑素皮质素途径。到目前为止，能够减少肥胖的“安全有效”药物的数量非常有限，目前正在上市或正在开发中。导致肥胖的原因有很多，但一个关键的障碍是，并不是所有与肥胖有关的分子、因子、蛋白质、受体和途径都被识别出来，并从机制上描述了它们的特征。贝塔防御素就是一个这样的例子。我们的工作假设是，内源性的β-防御素配体调节黑素皮质素受体的功能。目前尚不清楚β-防御素与黑素皮质素受体的具体分子相互作用和相互作用机制。它们是激动剂还是拮抗剂？受体亚型的选择性特征是什么？假定的配体-受体相互作用是什么？提出的回答上述问题的多学科方法包括化学和体外受体药理学。这项建议旨在阐明这个新的内源性黑素皮质素受体配体家族，获得基础知识，并开发分子探针用于确定它们与肥胖和2型糖尿病的潜在关系。

DESCRIPTION (provided by applicant): Obesity afflicts millions of people, and is a major risk factor for Type II diabetes and morbidity. The melanocortin pathway has been clearly identified in mice and humans to be involved in the regulation of obesity and energy homeostasis. Five melanocortin genetic factors that have been identified as being involved in energy homeostasis (the proopiomelanocortin agonists, Agouti and Agouti-related protein antagonists, and the melanocortin-4 receptor and the melanocortin-3 receptor proteins). In 2007, endogenous beta-defensin peptides were reported to participate in the melanocortin pathway. To date, a very limited number of "safe and effective" drugs that result in decreased obesity are currently marketed or in the pipeline. There are many reasons for this, however a critical obstacle is that not all the molecules, factors, proteins, receptors, and pathways that are involved in obesity have been identified and mechanistically characterized. One such example is the beta-defensins. Our working hypothesis is that the endogenous beta-defensin ligands regulate melanocortin receptor function. It is unclear the specific molecular interactions and mechanisms by which the beta-defensins interact with the melanocortin receptors. Are they agonists or antagonists? What are the receptor subtype selectivity profiles? What are the putative ligand-receptor interactions? The proposed multidisciplinary approaches to answer the above questions include chemistry and in vitro receptor pharmacology. This proposal seeks to clarify this novel endogenous melanocortin receptor ligand family, gain fundamental knowledge, and develop molecular probes to use to determine their potential involvement with obesity and Type 2 diabetes.