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 和下丘脑-垂体-肾上腺(HPA)的病理生理学 -性腺(HPG)轴。应激相关激素在正常和非应激反应中的作用 正在对疾病状态进行检查，并对其进行临床应用 人们在寻找荷尔蒙。促肾上腺皮质激素结构的发现 促排卵激素(CRH)及其灵敏检测方法的发展 检测HPA和HPG相关激素及其受体导致 这一领域的快速发展。三个方面取得了重大进展 领域：1)CRH的临床应用：一种绵羊(O)CRH刺激 已经开发出一种有助于鉴别诊断的检测方法。 肾上腺功能不全、库欣综合征和假性库欣状态 (精神性皮质醇增多症)。脑脊液促肾上腺皮质激素释放激素试验和/或测量 CRH增加了我们对库欣病的病理生理学的了解 综合症，忧郁症，儿童期性虐待， 非典型/季节性抑郁，慢性疲劳/纤维肌痛综合征， 糖尿病、类风湿性关节炎和产后 忧郁/抑郁综合症。2)通过以下方式调节轴线 已对神经递质、神经肽和糖皮质激素进行了研究 体内和/或体外。妊娠晚期妇女和运动员 在静息状态下有一个功能亢进的垂体-肾上腺轴。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 已经对监管进行了研究。它有2个积极的推动者和回应 对雌激素的积极作用，为性行为提供了一个潜在的解释 以CRH异常为特征的精神疾病的二型性 分泌物。3)HPA和HPG轴激素的作用和作用。 糖皮质激素抵抗是一种常染色体隐性或显性疾病 与糖皮质激素受体异常有关。我们有 通过定义，阐明了该综合征的分子病理生理学 糖皮质激素受体基因突变和/或缺失导致 患者组织中的受体异常或减少。这个 盐皮质激素受体及其对阿米洛利敏感的亚单位 散发性假性低醛固酮增多症患者的钠通道研究 或对盐皮质激素耐药。经典的互动 糖皮质激素受体及其非配基天然结合 同源糖皮质激素受体β(GRbeta)彼此之间以及与 热休克蛋白和糖皮质激素反应元件(GRE) 研究了DNA，以及GRβ在人类中的重要性 生理学和病理生理学。我们已经阐明了分子 常染色体隐性遗传性ACTH抵抗的病理生理学研究 以孤立性糖皮质激素缺乏为特征的疾病，通过定义 ACTH受体基因异常。我们已经澄清了 睾丸和卵巢耐药的分子病理生理学研究 通过定义黄体生成素受体的异常来确定黄体生成素 吉恩。我们已经定位了卡尼复合体的基因，一种多重的 肿瘤/雀斑样变综合征，位于染色体2p16，并有 将其定性为原癌基因。我们已经定义了分子 芳香酶过多综合征的缺陷。

In this project we seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. The role of stress-related hormones in normal and disease states is being examined, and clinical applications for these hormones are sought. The discovery of the structure of corticotropin releasing hormone (CRH) and the development of sensitive assays for measuring HPA- and HPG-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 (o) CRH 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 oCRH test and/or measurements of CSF CRH have increased our understanding of the pathophysiology of Cushing's syndrome, melancholic depression, childhood sexual abuse, atypical/seasonal depression, the chronic fatigue/fibromyalgia syndromes, diabetes mellitus, rheumatoid arthritis, and the postpartum blues/depression syndromes. 2) The regulation of the axis by neurotransmitters, neuropeptides, and glucocorticoids has been studied in vivo and/or in vitro. Third trimester pregnant women and athletes have a hyperfunctional pituitary- adrenal axis in the resting state. The hCRH gene 5' regulatory region has been cloned and sequenced and its regulation has been studied. It has 2 active promoters and responds positively to estrogens, providing a potential explanation for the sexual dimorphism of psychiatric diseases characterized by aberrations in CRH secretion. 3) Roles and actions of HPA and HPG axes hormones. Glucocorticoid resistance is an autosomal recessive or dominant disease associated with abnormalities of the glucocorticoid receptor. 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 mineralocorticoid receptor and the subunits of the amiloride-sensitive sodium channel are studied in sporadic cases of pseudohypoaldosteronism or mineralocorticoid resistance. The interaction of the classic glucocorticoid receptor (GRalpha) and its nonligand binding natural homolog glucocorticoid receptor beta (GRbeta) with each other and with the heat-shock proteins and glucocorticoid-responsive elements (GREs) of the DNA are studied, as the well as the importance of GRbeta in human physiology and pathophysiology. We have elucidated the molecular pathophysiology of hereditary ACTH resistance, an autosomal recessive disorder characterized by isolated glucocorticoid deficiency, by defining abnormalities of the ACTH receptor gene. We have elucidated the molecular pathophysiology of testicular and ovarian resistance to luteinizing hormone (LH) by defining abnormalities of the LH receptor gene. We have localized the gene for Carney Complex, a multiple neoplasia/lentiginosis syndrome, on chromosome 2p16, and have characterized it as a protooncogene. We have defined the molecular defect in the excessive aromatase syndrome.