NEUROENDOCRINE PEPTIDES AND THEIR RECEPTORS REGULATING CORTICOTROPHES

描述：（直接取自应用程序）促肾上腺皮质激素释放 因子在调节适应性反应中起着关键作用， 内分泌、中枢神经和免疫系统对压力的反应。在过去的授予 1999年，本项目对CRF进行了表征，并克隆了第一个CRF受体 （CRF-R），一种与腺苷酸环化酶连接的G蛋白偶联受体。证据 来自受体嵌合体和突变体的研究表明， 受体的第一胞外结构域用于初始配体结合，但不 用于受体激活。我们建议表征结合位点内的 受体的第一个胞外结构域，并探索关于 通过肽的特异性N-末端结构域激活受体 配体。我们还将研究配体非依赖性或配体依赖性的持续性 我们观察到的野生型受体或配体/受体的活性 嵌合体 自提交上一份竞争性投标书以来，我们和其他机构 鉴定了来自第二个基因CRF-R2的受体，令人惊讶的是， 仅对CRF具有中等亲和力，但对CRF相关肽具有高亲和力 低等脊椎动物，尾加压素和sauvagine。一种新的CRF相关肽， 我们命名为urocortin，然后从大鼠中脑和人类基因组中克隆， 文库;合成的复制品具有高亲和力，可以在功能上 在体外和体内刺激1型和2型CRF受体。我们有 存在其他配体的解剖学和免疫学证据， 与尾加压素和sauvagine有关，并建议鉴定它们。的作用 CRF-R2及其已知和未知配体将在 我们将重点讨论旁分泌的相互作用。最后我们将 在不同组织中尿皮质素和CRF-R2表达改变的扩展观察 饱足状态，并探讨这种受体及其配体在 介导对瘦素的中枢反应。 在该方案的范围内，该项目的进展应继续， 产生关于分子性质、调节和生理的信息， CRF家族的配体和受体的作用，并提供有关 内分泌、代谢和压力相关疾病。

Description: (Taken directly from the application) Corticotropin Releasing Factor plays key roles in the modulation of adaptive responses of the endocrine, central nervous and immune systems to stress. In previous granting periods, this Project characterized CRF and cloned the first CRF receptor (CRF-R), a G-protein coupled receptor linked to adenylate cyclase. Evidence derived from receptor chimeras and mutants points to the importance of the first extracellular domain of the receptor for initial ligand binding but not for receptor activation. We propose to characterize binding sites within the first extracellular domain of the receptor and to explore hypotheses regarding activation of the receptor by specific N-terminal domains of the peptide ligand. We will also examine ligand-independent or ligand-dependent persistent activities that we have observed with wild type receptors or ligand/receptor chimeras. Since submission of the last competitive proposal, we and others have identified receptors derived from a second gene, CRF-R2, which surprisingly had only modest affinity for CRF, but high affinity for CRF-related peptides from lower vertebrates, urotensin and sauvagine. A novel CRF-related peptide, which we named urocortin, was then cloned from rat midbrain and human genomic libraries; the synthetic replicate has high affinity and can functionally stimulate both type 1 and 2 CRF receptors in vitro and in vivo. We have anatomic and immunologic evidence for the existence of additional ligands, related to urotensin and sauvagine and propose to identify them. The roles of CRF-R2 and its known and unknown ligand(s) will be explored within the pituitary where we will focus on paracrine interactions. Finally, we will extend observations of altered urocortin and CRF-R2 expression in different satiety states and explore the importance of this receptor and its ligands in mediating central responses to leptin. In the context of the Program, progress in this Project should continue to yield information concerning the molecular nature, regulation and physiologic roles of ligands and receptors of the CRF family and provide insight regarding endocrine, metabolic and stress-related diseases.