PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

在这个项目中，我们试图推进对生理学和 下丘脑-垂体-肾上腺轴的病理生理学。的作用 正在检测正常和疾病状态下的压力相关荷尔蒙，以及 寻求这些激素的临床应用。最新的发现 促肾上腺皮质激素释放激素(CRH)的结构和 检测应激相关激素和蛋白质的灵敏分析方法的发展 它们的受体在这一领域取得了快速进展。重大进展 在三个方面取得了进展：1)CRH的临床应用 促肾上腺皮质激素释放激素(OCRH)刺激试验已被开发出来，可用于 肾上腺皮质功能不全、库欣综合征和 伪库欣状态(精神性皮质醇亢进症)。人类促性腺激素释放激素 (HCRH)类似物在研究垂体-肾上腺生理学方面是有用的 轴心。OCRH刺激性试验和脑脊液CRH测定增加 我们对忧郁型库欣综合征病理生理学的认识 抑郁症，非典型抑郁症，季节性抑郁症，经前 紧张综合征、神经性厌食症、慢性疲劳综合征和晚期- 先发先天性肾上腺增生症。2)通过以下方式调节轴线 阿片类药物、加压素、催产素、糖皮质激素、二十烷类化合物、血小板 激活因子、肿瘤坏死因子-α、缩胆囊素 (CCK)、神经肽Y、苯二氮类激动剂和拮抗剂以及甲状腺 激素已经在体内和/或体外进行了研究。神经递质和 下丘脑CRH分泌的反馈调节也已在 体外培养。妊娠晚期妇女和运动员有功能亢进症 垂体-肾上腺轴处于测试状态。下丘脑--垂体-- 肾上腺轴反应性和人格特征在 发展中的青少年。HCRH基因5‘调控区已被克隆 并对其进行了测序，其调控正在研究中。3)的角色和行动 糖皮质激素：糖皮质激素对心血管的影响 系统在手术期间的应激仅仅是允许的。外科压力是 与ACTH的持续和搏动性分泌有关。糖皮质激素 抗性是一种常染色体隐性遗传或显性疾病，与 正常大小的糖皮质激素受体蛋白，其亲和力降低 糖皮质激素和正常大小的mRNA。我们找到了一个非保守派 类固醇结合区的点突变(Asp--&Gt；Val) 糖皮质激素受体，导致细胞亲和力下降 糖皮质激素受体和减少糖皮质激素的作用。几个 目前正在研究不同的家族和不同的分子机制。 糖皮质激素耐药性正在被发现。两人之间的相互作用 对糖皮质激素受体与热休克蛋白的关系进行了研究。

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 testing 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: 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 or dominant disease associated with normal size glucocorticoid receptor protein that has decreased affinity for glucocorticoids and normal size mRNA. We have found a nonconservative 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. Several kindreds are being studied and different molecular mechanisms of glucocorticoid resistance are being found. The interaction of the glucocorticoid receptor with the heat-shock proteins is studied.