CRH BINDING PROTEIN AND OBESITY

大脑促肾上腺皮质激素释放激素(CRH)的减少可能是原因之一 肥胖症患者的病理性摄食行为和代谢率 相关的代谢紊乱。Neurocrine发现了一种新的蛋白质 在死后的人脑中，高水平的CRH结合并失活 亲和力(CRH结合蛋白；CRH-BP) 与能量平衡的调节有关。多肽配体 将CRH从CRH-BP中分离出来补充大脑中“游离CRF”和 在肥胖动物模型中表现出显著的拟交感神经特性。 平行研究中的神经分泌生物科学正在优化非肽CRH- BP拮抗剂的体外效力和体内疗效 全身性给药后的啮齿动物。目前的建议是 致力于识别和描述在何种程度上 代谢紊乱的临床前和临床模型是易感的 脑促肾上腺皮质激素释放激素和垂体-肾上腺的手法治疗 应力轴。对最终用药有影响的两个数据集 开发将产生：L)CRH的临床前验证 动物体内的受体激动剂和CRH结合蛋白配体抑制剂 为人类肥胖和肥胖模型提供预测有效性的模型 2)生理参数的临床识别与细化 它们定义了压力和下丘脑-垂体-肾上腺的作用 在一系列人类代谢紊乱中的激活。

Decreases in brain corticotropin-releasing hormone (CRH) may contribute to pathological feeding behavior and metabolic rate seen in obesity and related metabolic disorders. Neurocrine has identified a novel protein in postmortem human brain which binds and inactivates CRH with high affinity (CRH-binding protein; CRH-BP) within brain areas that are implicated in the regulation of energy balance. Peptide ligands that dissociate CRH from the CRH-BP replenish brain levels of "free CRF" and exert significant sympathomimetic properties in animal models of obesity. Neurocrine Biosciences in parallel studies is optimizing non-peptide CRH- BP antagonists for both in vitro potency as well as in vivo efficacy in rodents following systemic administration. The present proposal is devoted to identifying and characterizing the extent to which the preclinical and clinical models of metabolic disorders are susceptible to modification via manipulation of brain CRH and pituitary-adrenal stress axes. Two data sets with implications for eventual medications development will be generated: l) the preclinical validation of CRH receptor agonists and CRH-binding protein ligand inhibitors in animal models which provide predictive validity for human models of obesity and 2) the clinical identification and refinement of physiological parameters which define the role of stress and hypothalamo-pituitary-adrenal activation in a constellation of human metabolic disorders.