PSYCHOBIOLOGY OF CORTICOTROPIN-RELEASING FACTOR

描述：(改编自申请人的摘要)本申请书是 NIH MH-42088竞争性续签申请，寻求五年支持， 这将代表这个关于心理生物学的项目的第15-19年 促肾上腺皮质激素释放因子(CRF)在过去的几年里，这笔赠款 为含CRF神经元在脑内的卓越作用提供了大量证据 调解反应，相当详细地描述了 CRF在哺乳动物中枢神经系统中的神经转导作用，可能是大多数 重要的是，促进了支持Dah基础的蓬勃发展 假设CRF在重度抑郁症患者中分泌过多。的确， 来自该实验室和其他实验室的贡献使用各种 多学科的方法提供了明确的证据 重度抑郁症患者神经元中含促肾上腺皮质激素释放激素的过度活动 尤其是那些患有严重抑郁症的患者。目前的提案旨在 将这项工作在很大程度上基于 目前的资助期(目标是I&2也朝着新的方向发展(遗传学 目标3和4)。具体地说，调查人员希望继续尸检 脑组织研究以进一步表征含CRF的改变 CRF和CRF中的神经元和含CRF受体的神经元 受体mRNA的表达，以及关注CRF2受体和 尿皮质激素与小分子、非肽CRF1受体的研究进展 拮抗剂已经在一定程度上发生了，因为调查人员在 这块地。随着它们的可用性不断提高，行为、内分泌和 慢性应用CRF1受体的神经化学反应 对抗者将被描述为。此外，对停止使用的反应 将对这些化合物进行评估。在一种新的抑郁症动物模型中 基于高度敏感的强迫游泳测试中的敏感应力 对于所有类别的抗抑郁药，调查人员将确定 CRF1受体拮抗剂表现出抗抑郁的特征。此外，还有 这种动物中枢神经系统CRF神经元系统和受体的变化 模特？因为有证据表明，CRF功能改变似乎是 对焦虑和/或抑郁的表型负有至少部分责任 一些动物模型，研究人员会绘制数量性状基因座图 (QTL)控制CRF系统的表达。这些研究将提供 CRF神经系统在慢性肾小球疾病病理生理中作用的新信息 全身性CRF1受体拮抗剂对抑郁动物模型的影响 行政管理。

DESCRIPTION: (Adapted from applicant's abstract) This application is the competitive renewal application of NIH MH-42088, seeking five years of support, which would represent years 15-19 of this project on the Psychobiology of Corticotropin-Releasing Factor (CRF). In the past years, this grant has provided much evidence for a preeminent role for CRF-containing neurons in mediating the response, characterized in considerable detail the neurotransrnitter role of CRF in the mammalian CNS, and perhaps most importantly, contributed to the burgeoning dah base which supports the hypothesis that CRF is hypersecreted in patients with major depression. Indeed, contributions from this and other laboratories using a variety of multidisciplinary approaches have provided unequivocal evidence for hyperactivity of CRF-containing in neurons patients with major depression, particularly those patients with severe depression. The current proposal seeks to extend this work in directions largely based upon findings obtained during the current funding period (aims I & 2 in a new direction as well (genetics aims 3 & 4). Specifically, the investigators wish to continue the postmortem brain tissue studies to further characterize that alterations in CRF-containing neurons and CRF receptor-containing neurons by scrutinizing CRF and CRF receptor mRNA expression, as well as focusing on the CRF2 receptor and urocortin The development of small molecule, non-peptide CRF1 receptor antagonists has occurred to some extent due to the investigators progress in this field. With their increasing availability, the behavioral, endocrine, and neurochemical responses chronic administration of these CRF1 receptor antagonists will be characterized. Moreover, the responses to discontinuation of these compounds will be assessed. In a novel animal model of depression based upon sensitivity stress in the forced-swim test that is highly sensitive to all classes of antidepressants, the investigators will determine whether CRF1 receptor antagonists exhibit an antidepressant profile. Moreover, are alterations in CNS CRF neuronal systems and receptors present in this animal model? Because evidence suggests that altered CRF function appears to be responsible, at least in part, for the anxiety and/or depression phenotype in some animal models, the investigators will map the quantitative trait loci (QTL) that control the expression of the CRF system. These studies will provide novel information on the role of CRF nepronal systems in the pathophysiology of depression, in animal models of systemic CRF1 receptor antagonist administration.