PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

在这个项目中，我们寻求推进对生理学的理解， 下丘脑-垂体-肾上腺（HPA）和- 性腺（HPG）轴。 应激相关激素在正常和 疾病状态正在研究中，这些疾病的临床应用 激素被寻找。 促肾上腺皮质激素结构的发现 释放激素（CRH）和敏感检测方法的开发 测量HPA和HPG相关激素及其受体， 这一领域的快速发展。 在三个方面取得了重大进展 领域：1）CRH的临床应用：绵羊（o）CRH刺激 已开发的测试是有用的鉴别诊断 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）。 oCRH测试和/或CSF测量 CRH增加了我们对库欣病病理生理的了解 综合症，精神抑郁症，儿童期性虐待， 非典型/季节性抑郁症，慢性疲劳/纤维肌痛综合征， 糖尿病类风湿性关节炎和产后 忧郁症/抑郁综合征。 2)轴的调节， 神经递质、神经肽和糖皮质激素已经被研究 在体内和/或体外。 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。 的 hCRH基因5'调控区已被克隆和测序，其 研究了规则。 它有2个积极的推动者， 积极的雌激素，提供了一个潜在的解释性的 以CRH畸变为特征的精神疾病的二态性 分泌物 3)HPA轴和HPG轴激素的作用和地位。 糖皮质激素抵抗是一种常染色体隐性或显性遗传疾病 与糖皮质激素受体异常有关。 我们有 阐明了这种综合征的分子病理生理学， 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。 的 盐皮质激素受体和阿米洛利敏感性 在假性醛固酮减少症散发病例中研究了钠通道 或盐皮质激素抵抗。 经典的互动 糖皮质激素受体（GR α）及其非配体结合天然 糖皮质激素受体β（GR β）彼此之间以及与 热休克蛋白和糖皮质激素反应元件（GRES） 研究了GR~（3+）在人类遗传学中的重要性， 生理学和病理生理学。 我们已经阐明了 遗传性ACTH抵抗的病理生理学，一种常染色体隐性 以孤立性糖皮质激素缺乏为特征的疾病，通过定义 促肾上腺皮质激素受体基因异常。 我们已经阐明了 睾丸和卵巢抵抗的分子病理生理学 黄体生成素（LH）通过定义LH受体异常 基因 我们已经定位了卡尼复合体的基因， 肿瘤/雀斑样痣综合征，位于染色体2 p16上。

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 GR~ 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.