GENETIC ANALYSIS OF CORTICOTROPIN RELEASING HORMONE

促肾上腺皮质激素释放激素的基因分析

• 批准号: 2134122
• 负责人: Louis J Muglia
• 金额: $ 8.76万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2134122
• 关键词: T lymphocyte; adrenalectomy; cell line; cell type; circadian rhythms; corticotropin releasing factor; cytokine; endocrine disorder; gene expression; genetic manipulation; genetically modified animals; hormone regulation /control mechanism; hypothalamic pituitary axis; immune system; inflammation; laboratory mouse; mitogens; molecular genetics; neuroendocrine system; neuroimmunomodulation; pituitary adrenal axis; stress; temperature sensitive mutant; tissue /cell culture; transfection

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.

该应用程序的总体目标是提高我们对 皮质激素释放激素的功能和调节。这 下丘脑 - 垂体 - 肾上腺（HPA）轴是一个重要的系统介导 人体对压力的许多反应，CRH是 HPA轴的调节。 CRH在 与ACTH释放的其他调节剂进行比较，例如加压素或 但是，儿茶酚胺目前尚不清楚。除了它在 ACTH释放的调节，CRH可能具有其他重要功能。 CRH 它的受体被广泛分布在大脑中，它可能充当 神经调节剂，可能介导某些形式的与压力相关的行为。 CRH也存在于免疫系统中，在该系统中已显示 抑制和增强炎症反应。法规的研究 这些生理角色中的CRH合成和释放已受到阻碍 通过合适的细胞模型的不可用。解决这些 问题，提出了三条调查。首先，缺乏CRH 将创建小鼠模型，使内源性鼠CRH基因失活 通过胚胎干细胞中的同源重组。使用此模型， CRH在垂体皮质营养发展中的作用和 将评估HPA轴的HPA轴和昼夜节律刺激。 第二， 永生的产生CRH的细胞系，直接研究 CRH释放，并提供合适的模型系统来研究 将建立CRM法规。第三，功能和调节 将研究在免疫系统中合成的CRH。这 赞助商Joseph Majzoub博士是分子的公认领导者 CRH的生物学。 大卫·怀特（David Wight）博士，合作开发 转基因小鼠系已成功生成许多转基因 过去的动物。 Raif Geha博士，他将担任顾问 CRH免疫功能，是一位著名的免疫学家 免疫激活机制的专业知识。提出的研究允许 身体对压力的反应的关键方面的定义，而 让我培训胚胎操纵和基因的技术 转移技术。这些技术将是我的长期目标的核心 研究神经内分泌系统的发展。