Role of the CRF2 Receptor in Ingestive Behavior

描述(由申请人提供)： 在美国，超重和肥胖的流行是流行病。肥胖和超重是主要的公共卫生问题，每年导致全国约30万人死亡，医疗成本高达1170亿美元。长期服用厌食剂是一种行之有效的体重控制方法。为了识别药物靶点，一个有希望的方法是更好地了解摄食行为的神经化学。虽然人们早就知道促肾上腺皮质激素释放因子(CRF)家族的多肽在中枢给药时会减少食物摄入量，但它们的作用机制仍不清楚。CRF和urocortin是CRF多肽家族中第一个和第二个被鉴定的哺乳动物成员。这些多肽中的每一个都是非选择性的，以相似的亲和力结合两种哺乳动物CRF受体。由于CRF受体的重叠分布和可用的多肽配体的非选择性，CRF1和CRF2受体在摄食调节中的相对作用仍不清楚。大脑CRF1受体介导身体应激样反应。因此，CRF1介导的厌食症可能只是反映了继发于应激样状态的非特异性摄食抑制。这种担忧限制了CRF1受体作为肥胖药物靶点的可行性。然而，一些发现激发了人们对CRF2受体在食欲调节中的作用的兴趣。不幸的是，CRF2受体的选择性配体还没有出现，这排除了它在摄食行为中所起作用的药理学特征。最近，两个小组独立地发现了编码哺乳动物CRF/UCN相关多肽的基因，这些基因在进化上彼此不同，也与CRF和UCN不同。它们是已知的第一种直接的、高选择性的CRF2受体激动剂。其中，小鼠UCN III是选择性最强的。与此同时，第一个有效、高选择性和长效的CRF2受体拮抗剂--芦荟素2-B-已经开发出来。目前的建议使用这些工具来探索大脑CRF2受体的摄取功能。此外，目前还不清楚CRF2受体是否也有CRF1受体激活的不良后果。CRF2介导的厌食症的中心作用部位和生理作用也尚不清楚。拟议的研究也将解决这些问题，以更好地了解CRF2受体在摄食行为中的作用。

DESCRIPTION (provided by applicant): The prevalence of overweight and obesity in the United States is epidemic. Obesity and overweight are major public health problems, annually responsible for approximately 300,000 deaths and health costs of $117 billion nationally. Long-term administration of anorectics is one proven approach to weight control. To identify drug targets, a promising approach is to understand better the neurochemistry of feeding behavior. While it has long been known that peptides of the corticotropin-releasing factor (CRF) family reduce food intake when given centrally, their mechanisms of action remain poorly understood. CRF and urocortin were the first and second mammalian members of the CRF peptide family to be identified. Each of these peptides is non-selective, binding both mammalian CRF receptors with similar affinities. Because of the overlapping distribution of CRF receptors and the non-selectivity of available peptide ligands, the relative roles of CRF1 and CRF2_ receptors in the regulation of feeding have remained elusive. Brain CRF1 receptors mediate bodily stress-like responses. As such, CRFl-mediated anorexia may simply reflect non-specific feeding suppression secondary to a stress-like state. This concern limits the viability of the CRF1 receptor as a drug target for obesity. Several findings, however, have spurred interest in the role of the CRF2 receptor in appetite regulation. Unfortunately, selective ligands for the CRF2 receptor have not been available, precluding pharmacological characterization of its role in feeding behavior. Recently, two groups independently identified genes encoding mammalian CRF/Ucn-related peptides that are evolutionarily distinct from one another as well as from CRF and Ucn. They are the first known direct, highly selective CRF2 receptor agonists. Of them, murine Ucn III is the most selectively potent. Contemporaneously, the first potent, highly selective, and long acting CRF2 receptor antagonist -- astressin2-B -- has been developed. The present proposal uses these tools to probe the ingestive functions of brain CRF2 receptors. In addition, it is not clear whether the CRF2 receptor shares the adverse consequences of CRF1 receptor activation. The central sites of action and physiologic role for CRF2-mediated anorexia also remain unknown. The proposed studies will address these questions as well to understand better the role of the CRF2 receptor in feeding behavior.