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。的 下丘脑-垂体-肾上腺（HPA）轴是一个重要的系统， 许多身体对压力的反应，CRH是一个核心组成部分， HPA轴的调节。CRH的作用和相对重要性， 与ACTH释放的其他调节剂，例如加压素或 然而，目前对儿茶酚胺的认识还不清楚。除了在以下方面的作用外， 调节ACTH释放，CRH可能具有其他重要功能。CRH 其受体广泛分布在大脑中，在那里它可以作为 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既 抑制和增强炎症反应。调节研究 CRH的合成和释放在这些生理作用中受到阻碍 由于没有合适的细胞模型。解决这些 问题，提出了三条调查路线。首先，CRH缺乏 将建立小鼠模型，灭活内源性鼠CRH基因 通过胚胎干细胞中的同源重组。利用该模型 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促肾上腺皮质激素释放激素的反应 将评估HPA轴对压力和昼夜节律刺激的反应。 第二、 永生化CRH产生细胞系，以直接研究 CRH释放，并提供一个合适的模型系统与研究 将建立CRM规范。第三，功能与调控 将研究免疫系统内合成的CRH。的 发起人Joseph Majzoub博士是分子生物学领域公认的领导者， CRH生物学 大卫怀特博士，合作开发 转基因小鼠品系，已经成功地产生了许多转基因 动物在过去Raif Geha博士将担任 CRH的免疫功能，是一个突出的免疫学家与相当大的 免疫激活机制的专业知识。拟议的研究允许 身体对压力反应的一个关键方面的定义，而 让我能够接受胚胎操作和基因技术的训练 转让技术。这些技术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.