PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

在这个项目中，我们试图增进对生理学的理解 以及下丘脑-垂体-肾上腺轴的病理生理学。角色 在正常和疾病状态下的应激相关荷尔蒙 检查，并寻求这些激素的临床应用。这个 促肾上腺皮质激素释放激素结构的新发现 (CRH)和用于测量应力的灵敏分析的开发- 相关的激素和它们的受体导致了这方面的快速进展。 菲尔德。在三个方面取得了重大进展：1)临床 促肾上腺皮质激素释放激素的应用：绵羊促肾上腺皮质激素释放激素(OCRH)刺激试验 对肾上腺疾病的鉴别诊断有帮助 功能不全、库欣综合征和假性库欣状态 (精神性皮质醇增多症)。人类CRH(HCRH)类似物在 研究垂体-肾上腺轴的生理学。OCRH 脑脊液促肾上腺皮质激素释放激素刺激试验和测定增加了我们的 忧郁型库欣综合征的病理生理学认识 抑郁症，非典型抑郁症，季节性抑郁症，经前 紧张综合症，神经性厌食症，慢性疲劳综合症， 纤维肌痛、迟发性先天性肾上腺增生症、糖尿病 糖尿病和类风湿性关节炎。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 活化因子(PAF)、肿瘤坏死因子-α、白介素6、 CCK、神经肽Y、苯二氮类激动剂和 拮抗剂和甲状腺激素已经在体内和/或在 体外培养。下丘脑CRH的神经递质与反馈调节 体外和体内的分泌物也进行了检测。妊娠晚期 孕妇和运动员有功能亢进的垂体-肾上腺轴 处于休眠状态。下丘脑-垂体-肾上腺轴反应性和 人格特征与发育中的青少年有关联。这个 人促肾上腺皮质激素释放激素基因5‘调控区的克隆及序列分析 监管正在研究之中。它有2个积极的推动者和回应 对雌激素呈阳性反应，为 精神疾病的性别二型性，以精神错乱为特征 CRH分泌。3)糖皮质激素的作用和作用：手术应激 与ACTH的持续和搏动性分泌有关。 糖皮质激素抵抗是一种常染色体隐性或显性疾病 与糖皮质激素受体II型异常有关。 已经阐明了这种综合征的分子病理生理学 确定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。 糖皮质激素受体I型(盐皮质激素)在 几种对盐皮质激素有抵抗力的品种。的相互作用 研究了糖皮质激素受体与热休克蛋白的关系。 遗传性ACTH抵抗是一种常染色体隐性遗传性疾病 以脑垂体糖皮质激素缺乏为特征的。我们已经澄清了 通过定义异常来确定该综合征的分子病理生理学 ACTH受体基因。

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, fibromyalgia, late-onset congenital adrenal hyperplasia, diabetes mellitus and rheumatoid arthritis. 2) The regulation of the axis by opioids, vasopressin, oxytocin, glucocorticoids, eicosanoids, platelet activating factor (PAF), tumor necrosis factor - alpha, interleukin-6, 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 and in vivo. 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. It has 2 active promoters and responds positively to estrogens, providing a potential explantation for the sexual dimorphism of psychiatric diseases characterized by abberations in CRH secretion. 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. Hereditary ACTH resistance is an autosomal recessive disorder characterized by pituitary glucocorticoid deficiency. We have elucidated the molecular pathophysiology of this syndrome by defining abnormalities of the ACTH receptor gene.