Defensins as Melanocortin Ligands

描述（由申请人提供）：肥胖困扰着数百万人，是II型糖尿病和发病的主要危险因素。在小鼠和人类中，黑皮质素途径已被明确鉴定为参与肥胖和能量稳态的调节。已确定参与能量稳态的五种黑皮质素遗传因子（前阿黑皮素激动剂、Agonists和Agouti相关蛋白拮抗剂、黑皮质素-4受体和黑皮质素-3受体蛋白）。2007年，据报道内源性β-防御素肽参与黑皮质素途径。到目前为止，导致减少肥胖的“安全有效”药物的数量非常有限，目前已上市或正在开发中。这有许多原因，但一个关键的障碍是，并不是所有的分子，因子，蛋白质，受体，和参与肥胖的途径已被确定和机械特征。一个这样的例子是β-防御素。我们的工作假设是内源性β-防御素配体调节黑皮质素受体功能。目前还不清楚β-防御素与黑皮质素受体相互作用的具体分子相互作用和机制。它们是激动剂还是拮抗剂？受体亚型选择性特征是什么？假定的配体-受体相互作用是什么？建议多学科的方法来回答上述问题，包括化学和体外受体药理学。该提案旨在澄清这种新型内源性黑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其与肥胖和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.