PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

下丘脑-垂体-肾上腺轴的生理学和病理生理学

• 批准号: 3842293
• 负责人: G P CHROUSOS
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3842293
• 关键词: Cushing's syndrome; adolescence (12-20); adrenal disorder; adrenal hyperplasia; anorexia nervosa; chronic fatigue syndrome; clinical depression; corticosteroid receptors; corticotropin releasing factor; endocrine disorder diagnosis; endocrine pharmacology; gene mutation; genetic disorder; genetic regulation; genetic regulatory element; gestational age; glucocorticoids; hormone regulation /control mechanism; human genetic material tag; human subject; human tissue; hypothalamic pituitary axis; molecular cloning; nutrition related tag; peptide hormone analog; pituitary adrenal axis; pregnancy; premenstrual syndrome; seasonal affective disorder; stress proteins

In this project we seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary-adrenal axis. The role of stress-related hormones in normal and disease states is being examined, and clinical applications for these hormones are sought. The recent discovery of the structure of corticotropin releasing hormone (CRH) and the development of sensitive assays for measuring stress- related hormones and their receptors have led to rapid progress in this field. Major progress has been made in three areas: 1) Clinical applications of CRH: An ovine CRH (oCRH) stimulation test has been developed that is useful in the differential diagnosis of adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's states (psychiatric hypercortisolism). The human CRH (hCRH) analog is useful in studying the physiology of the pituitary-adrenal axis. The oCRH stimulation test and measurement of CSF CRH have increased our understanding of the pathophysiology of Cushing's syndrome, melancholic depression, atypical depression, seasonal depression, and the premenstrual tension syndrome, anorexia nervosa, the chronic fatigue syndrome and late-onset congenital adrenal hyperplasia. 2) The regulation of the axis by opioids, vasopressin, oxytocin, glucocorticoids, eicosanoids, platelet activating factor (PAF), tumor necrosis factor - alpha, cholecystokinin (CCK), neuropeptide Y, benzodiazepine agonists and antagonists and thyroid hormones has been studied in vivo and/or in vitro. Neurotransmitter and feedback regulation of hypothalamic CRH secretion has also been examined in vitro. Third trimester pregnant women and athletes have a hyperfunctional pituitary-adrenal axis in the resting state. Hypothalamic-pituitary-adrenal axis reactivity and personality traits have been correlated in developing adolescents. The hCRH gene 5' regulatory region has been cloned and sequenced and its regulation is being studied. 3) Role and actions of glucocorticoids: Surgical Stress is associated with continuous and pulsatile secretion of ACTH. Glucocorticoid resistance in an autosomal recessive or dominant disease associated with abnormalities of the glucocorticoid receptor type II. We have elucidated the molecular pathophysiology of this syndrome by defining mutations and/or deletion of the glucocorticoid receptor gene leading to abnormal or decreased receptors in the tissues of patients. The glucocorticoid receptor type I (mineralocorticoid) is studied in several kindreds with mineralocorticoid resistance. The interaction of the glucocorticoid receptor with the heat-shock proteins is studied.

在这个项目中，我们试图提高对生理学的理解 下丘脑 - 垂体 - 肾上腺轴的病理生理学。角色 正常状态和疾病状态中与压力相关的激素正在 检查了这些激素的临床应用。这 最近发现皮质激素释放激素的结构 （CRH）和开发用于测量应力的敏感测定法 相关的激素及其受体在这方面取得了迅速的进步 场地。在三个领域取得了重大进展：1）临床 CRH的应用：卵CRH（OCRH）刺激测试已有 开发的，可用于肾上腺的鉴别诊断 功能不全，库欣综合症和伪库的状态 （精神科高皮层化学）。人CRH（HCRH）类似物在 研究垂体 - 肾上腺轴的生理学。 OCRH CSF CRH的刺激测试和测量增加了我们的 了解库欣综合症的病理生理学，忧郁症 抑郁症，非典型抑郁症，季节性抑郁症和 经前张力综合征，神经性厌食症，慢性疲劳 综合征和晚期先天性肾上腺增生。 2） 通过阿片类药物，加压素，催产素对轴调节轴。 糖皮质激素，类花生酸，血小板激活因子（PAF），肿瘤 坏死因子-Alpha，胆囊动蛋白（CCK），神经肽Y， 苯二氮卓类激动剂和拮抗剂和甲状腺激素已经是 在体内和/或体外研究。神经递质和反馈 还检查了下丘脑CRH分泌的调节 体外。三个月孕妇和运动员有一个 静息状态下的垂体性垂体高功能。 下丘脑 - 垂体 - 肾上腺轴反应性和人格特征 与发展青少年有关。 HCRH基因5' 调节区域已被克隆和测序，其调节是 正在研究。 3）糖皮质激素的作用和作用：手术应激 与ACTH的连续和脉动分泌有关。 常染色体隐性或显性疾病中的糖皮质激素耐药性 与II型糖皮质激素受体的异常有关。我们 已经阐明了该综合征的分子病理生理 定义糖皮质激素受体基因的突变和/或缺失 导致患者组织中受体异常或减少。 在研究中研究了糖皮质激素受体I型（矿物皮质激素） 几种具有矿物皮质耐药性的亲属。相互作用 研究了带有热震蛋白的糖皮质激素受体。