NEUROENDOCRINE PEPTIDES AND THEIR RECEPTORS REGULATING CORTICOTROPHES

描述：(直接取自应用程序)释放促肾上腺皮质激素 因子在调节机体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。在以前的批准中 期间，本项目确定了CRF的特征并克隆了第一个CRF受体 (CRF-R)，一种与腺苷环化酶连接的G蛋白偶联受体。证据 从受体嵌合体和突变体中衍生出来的表明了 受体的第一个胞外区，用于初始配体结合，但不是 用来激活受体。我们建议将结合部位的特征 第一个受体的胞外结构域，并探索关于 通过多肽的特定N-末端结构域激活受体 莱兰德。我们还将研究配体非依赖或配体依赖的持久性 我们观察到的野生型受体或配体/受体的活性 嵌合体。 自从提交最后一份竞争性提案以来，我们和其他人已经 发现的受体来自第二个基因，CRF-R2，令人惊讶的是 对CRF只有中等亲和力，但对来自 低等脊椎动物，尾加压素和苏维茵。一种新的CRF相关肽，其 我们命名为urocortin，然后从大鼠中脑和人类基因组中克隆出来 文库；合成复制具有很高的亲和力，并且可以在功能上 在体外和体内刺激1型和2型CRF受体。我们有 存在额外配体的解剖学和免疫学证据， 与尾加压素和苏维林有关，并建议对其进行鉴定。的角色 CRF-R2及其已知和未知配体(S)将在 我们将重点放在旁分泌相互作用的脑垂体。最后，我们会 Urocortin和CRF-R2在不同组织中表达变化的扩展观察 饱腹感状态，并探讨该受体及其配体在 调节瘦素的中枢反应。 在本方案的背景下，本项目的进展应继续 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，并提供关于 内分泌、代谢和应激相关疾病。

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.