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: 3778556
• 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/3778556
• 关键词: Cushing's syndrome; adolescence (12-20); adrenal disorder; adrenocorticotropic hormone; anorexia nervosa; autoimmune disorder; chronic fatigue syndrome; clinical depression; corticosteroid receptors; corticotropin releasing factor; endocrine disorder diagnosis; endocrine pharmacology; genetic disorder; genetic regulation; glucocorticoids; hormone regulation /control mechanism; human genetic material tag; human pregnant subject; human subject; hypothalamic pituitary axis; personality; pituitary adrenal axis; pregnancy; premenstrual syndrome; stress; Cushing's syndrome; adolescence (12-20); adrenal disorder; adrenocorticotropic hormone; anorexia nervosa; autoimmune disorder; chronic fatigue syndrome; clinical depression; corticosteroid receptors; corticotropin releasing factor; endocrine disorder diagnosis; endocrine pharmacology; genetic disorder; genetic regulation; glucocorticoids; hormone regulation /control mechanism; human genetic material tag; human pregnant subject; human subject; hypothalamic pituitary axis; personality; pituitary adrenal axis; pregnancy; premenstrual syndrome; stress

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, 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 is 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，我们旨在提高对生理学和 下丘脑 - 垂体 - 肾上腺轴的病理生理。 的作用 正在检查正常状态和疾病状态中与压力相关的激素，正在检查， 并寻求这些激素的临床应用。 最近 发现皮质激素释放激素（CRH）的结构和 开发用于测量应力相关激素的敏感测定法 他们的受体导致了这一领域的快速发展。 主要的 在三个领域取得了进展：1）CRH的临床应用： 已经开发了一个卵CRH（OCRH）刺激测试 肾上腺功能不全的鉴别诊断，库欣综合症， 和伪克什的状态（精神病性超皮质醇）。 人类CRH （HCRH）模拟可用于研究垂体的生理学 肾上腺轴。 CSF CRH的OCRH刺激测试和测量 增加了我们对库欣综合症病理生理学的理解， 忧郁的抑郁症，非典型抑郁症，季节性抑郁症， 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）法规 阿片类药物，加压素，催产素，糖皮质激素， 类类，血小板激活因子（PAF），肿瘤坏死因子 - Alpha，胆囊化蛋白（CCK），Neuropeptide Y，苯二氮卓激动剂和 在体内和/或体外研究了拮抗剂和甲状腺激素。 下丘脑CRH分泌的神经递质和反馈调节 还在体外检查了。 三个月孕妇和运动员 在静息状态下具有高功能垂体 - 肾上腺轴。 下丘脑 - 垂体 - 肾上腺轴反应性和人格特质具有 与发展的青少年有关。 HCRH基因5'调节 区域已被克隆和测序，正在研究其调节。 3）糖皮质激素的作用和作用：手术应激与 随着ACTH的连续和脉动分泌。 糖皮质激素 抵抗是一种常染色体隐性或主要疾病 II型糖皮质激素受体的异常。 我们已经阐明了 通过定义突变，该综合征的分子病理生理学 和/或缺失糖皮质激素受体基因，导致异常或 患者组织中受体减少。 糖皮质激素 研究受体I型（矿物皮质激素）在几种属性中进行了研究 矿物皮质激素耐药性。 糖皮质激素的相互作用 研究了带有热震蛋白的受体。