PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

在这个项目中，我们寻求促进对生理学的理解， 下丘脑-垂体-肾上腺轴的病理生理学。 的作用 正在检查正常和疾病状态下与压力有关的激素， 寻求这些激素的临床应用。最近发现 促肾上腺皮质激素释放激素（CRH）的结构， 开发用于测量与压力有关的激素的灵敏测定法， 它们的受体导致了这一领域的快速发展。重大进展 在三个方面取得了进展： 1)CRH的临床应用：绵羊CRH（oCRH）刺激试验， 已开发的是有用的鉴别诊断肾上腺 不足库欣综合征和假性库欣状态（精神病性 皮质醇增多症）。人CRH（hCRH）类似物可用于研究 垂体-肾上腺轴的生理学。oCRH刺激试验和 CSF CRH的测量增加了我们对 库欣综合征的病理生理学，非典型性抑郁症 抑郁症，季节性抑郁症，经前紧张综合征， 神经性厌食症、慢性疲劳综合征和迟发性先天性 肾上腺增生 2)阿片类药物，加压素，催产素， 糖皮质激素、血小板活化因子（PAF）、肿瘤坏死因子- α、胆囊收缩素（CCK）、神经肽Y、苯二氮卓激动剂和 已经在体内和/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 还在体外进行了检测。妊娠晚期孕妇和运动员 在静息状态下有功能亢进的垂体肾上腺轴。 下丘脑-垂体-肾上腺轴反应性和人格特质 与青少年的发育有关。hCRH基因5'调控 该区域已被克隆测序，其调控正在研究中。 3)糖皮质激素的作用和行动：糖皮质激素的影响， 心血管系统在手术压力下仅仅是允许的。 手术应激与持续和脉冲式分泌 促肾上腺皮质激素糖皮质激素抵抗是一种常染色体隐性遗传病 与正常大小的糖皮质激素受体蛋白相关， 对糖皮质激素和正常大小mRNA的亲和力降低。我们发现 类固醇结合结构域中的非保守点突变（Asp -->瓦尔） 糖皮质激素受体，导致亲和力下降， 糖皮质激素受体和糖皮质激素作用减弱。的 糖皮质激素受体与热休克蛋白的相互作用， 研究了

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, 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 sequenced and its regulation is being studied. 3) Role and actions of glucocorticoids: The effects of glucocorticoids upon the cardiovascular system during surgical stress are merely permissive. Surgical Stress is associated with continuous and pulsatile secretion of ACTH. Glucocorticoid resistance is an autosomal recessive disease associated with normal size glucocorticoid receptor protein that has decreased affinity for glucocorticoids and normal size mRNA. We have found a nonconserved point mutation (Asp --> Val) in the steroid binding domain of the glucocorticoid receptor which leads to a decrease in the affinity of the receptor for glucocorticoids and decreased glucocorticoid effect. The interaction of the glucocorticoid receptor with the heat-shock proteins is studied.