GENETIC ANALYSIS OF CORTICOTROPIN RELEASING HORMONE

本应用程序的总体目标是提高我们对 促肾上腺皮质激素释放激素的功能和调节。这个 摘要下丘脑-垂体-肾上腺轴是中枢神经系统的重要调节系统。 机体对压力的许多反应，而CRH是 HPA轴的调节。促肾上腺皮质激素释放激素的作用和相对重要性 与其他促肾上腺皮质激素释放调节剂的比较，如加压素或 然而，儿茶酚胺目前还不清楚。除了它在以下方面的作用 调节ACTH的释放，CRH可能发挥其他重要作用。CRH 和它的受体广泛分布在大脑中，在那里它可能起到 一种神经调节剂，可能调节某些形式的压力相关行为。 CRH也存在于免疫系统中，在那里它已经被证明是 抑制和增强炎症反应。关于规则的研究 CRH在这些生理作用中的合成和释放受到阻碍 由于无法获得合适的细胞模型。要解决这些问题 问题，提出了三条调查思路。首先，CRH缺乏 将内源性小鼠促肾上腺皮质激素释放激素基因失活 通过胚胎干细胞中的同源重组。在这种模式下， 促肾上腺皮质激素释放激素在垂体促肾上腺皮质激素细胞发育中的作用及对促肾上腺皮质激素的反应 HPA轴对应激和昼夜节律刺激的影响将被评估。第二, 永生化CRH产生细胞株直接研究促肾上腺皮质激素释放激素 CRH释放，并提供一个合适的模型系统进行研究 将建立客户关系管理法规。第三，法律法规的作用和规范 将对免疫系统内合成的CRH进行研究。这个 赞助商约瑟夫·马祖布博士是分子生物学领域公认的领导者。 CRH的生物学。大卫·鬼魂博士，合作开发 转基因小鼠品系，已成功培育出无数转基因 过去的动物。Raif Geha博士将担任 CRH的免疫功能，是著名免疫学家具有相当大的 在免疫激活机制方面的专业知识。拟议的研究允许 定义身体对压力反应的一个关键方面，而 让我接受了胚胎操作和基因技术方面的培训 转让技术。这些技巧将是我长期目标的核心 研究神经内分泌系统的发展。

The overall goals of this application are to improve our understanding of both the function and regulation of corticotropin-releasing hormone. The hypothalamic-pituitary-adrenal (HPA) axis is an important system mediating many of the body's responses to stress, and CRH is a central component in regulation of the HPA axis. The role and relative importance of CRH in comparison with other regulators of ACTH release, e.g. vasopressin or catecholamines are, however, currently unclear. In addition to its role in regulation of ACTH release, CRH may serve other important functions. CRH and its receptor are widely distributed in the brain, where it may act as a neuromodulator, perhaps mediating some forms of stress-related behavior. CRH is also present in the immune system, where it has been shown to both suppress and augment inflammatory reactions. The study of the regulation of CRH synthesis and release in these physiologic roles has been hampered by the unavailability of suitable cellular models. To address these issues, three lines of investigation are proposed. First, a CRH-deficient mouse model will be created inactivating the endogenous murine CRH gene via homologous recombination in embryonic stem cells. With this model, the role of CRH in development of pituitary corticotrophs and the response of the HPA axis to stress and circadian stimuli will be evaluated. Second, immortalized CRH-producing cell lines to directly investigate mediators of CRH release, and to provide a suitable model system with which to study CRM regulation will be established. Third, the function and regulation of CRH synthesized within the immune system will be investigated. The sponsor, Dr. Joseph Majzoub, is a recognized leader in the molecular biology of CRH. Dr. David Wight, collaborating on development of transgenic mouse lines, has successfully generated numerous transgenic animals in the past. Dr. Raif Geha, who will serve as a consultant on the immune function of CRH, is a prominent immunologist with considerable expertise on mechanisms of immune activation. The proposed studies allow definition of a crucial aspect of the body's response to stress, while allowing me training in techniques of embryo manipulation and gene transfer technology. These techniques will be central to my long term goal of studying the development of the neuroendocrine system.