PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

下丘脑-垂体-肾上腺轴的生理学和病理生理学

• 批准号: 6108012
• 负责人: G P CHROUSOS
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6108012
• 关键词: adrenocorticotropic hormone; aromatase; asthma; clinical research; corticosteroid receptors; corticotropin releasing factor; depression; gender difference; gene deletion mutation; hormone regulation /control mechanism; human genetic material tag; human subject; hypoaldosteronism; hypothalamic pituitary adrenal axis; hypothalamic pituitary axis; luteinizing hormone; mood disorders; pituitary gonadal axis; protooncogene; puerperal disorder; receptor binding; receptor expression; sodium channel; steroid hormone receptor; stress proteins

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. Several developmental/psychiatric disorders, including melancholic depression and anorexia nervosa have been associated with increased corticotropin-releasing hormone (CRH) secretion. We recently demonstrated that the postpartum blues/depression syndrome is characterized by transient profound hypoactivity of the stress system, which explains not only the mood disorder but also the propensity of these patients to develop autoimmune diseases. We also found the hCRH gene 5' regulatory region responds positively to estrogens, providing a potential explanation for the sexual dimorphism of psychiatric diseases characterized by aberrations in CRH secretion. We are currently performing preclinical studies with a newly discovered nonpeptide, oral CRH antagonist, antalarmin. 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 deletions 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 were studied in sporadic cases of pseudohypoaldosteronism or mineralocorticoid resistance and the defect was localized in the beta and gamma subunits of this channel. The interactions 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 well as the importance of GRbeta in human physiology and pathophysiology. We have found an abnormal expression of the beta vs. the alpha isoform of the glucocorticoid receptor in patients with glucocorticoid resistant asthma. We have determined that Vpr, a 15KD protein product of HIV-1, is a coregulator of the glucocorticoid, androgen and estrogen receptors, the presence of which explain some of the clinical features and pathogenesis of AIDS. 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 two genes for Carney Complex, a multiple neoplasia/lentiginosis syndrome, on chromosome 2p16 and 17q. We have defined the molecular defect in the excessive aromatase syndrome, a novel promoter aberrantly and ectopically expressed in affected individuals.

在这个项目中，我们寻求促进理解， 下丘脑的生理学和病理生理学 垂体-肾上腺（HPA）和性腺（HPG）轴。的作用 正常和疾病状态下与压力相关的激素正在被 检查，并寻求这些激素的临床应用。 几种发育/精神疾病，包括神经性 抑郁症和神经性厌食症 促肾上腺皮质激素释放激素（CRH）分泌增加。我们 最近的研究表明，产后抑郁症 综合征的特点是短暂的深度功能减退， 压力系统，这不仅解释了情绪障碍， 这些患者发展自身免疫性疾病的倾向。 我们还发现hCRH基因5'端调控区对 积极的雌激素，提供了一个潜在的解释， 精神疾病的性二态性特征， CRH分泌异常。我们目前正在执行 一种新发现的非肽类口服CRH的临床前研究 拮抗剂，antalarmin。糖皮质激素抵抗是一种常染色体 隐性或显性疾病与异常的 糖皮质激素受体我们已经阐明了 通过定义突变和/或 糖皮质激素受体基因缺失导致异常 或者患者组织中的受体减少。的 盐皮质激素受体及其亚单位 阿米洛利敏感性钠通道的研究在散发病例 假性醛固酮减少症或盐皮质激素抵抗， 这种缺陷局限于β和γ亚基， 频道经典糖皮质激素受体的相互作用 （GR α）及其非配体结合天然同系物 糖皮质激素受体β（Grbeta）与彼此和与 热休克蛋白和糖皮质激素反应元件 （GRES）的DNA进行了研究，以及重要性， 人体生理学和病理生理学中的GR β。我们发现 β与α亚型的异常表达， 糖皮质激素抵抗患者的糖皮质激素受体 哮喘我们已经确定Vpr，一个15 KD的蛋白产物， HIV-1是糖皮质激素、雄激素和 雌激素受体，它的存在解释了一些 艾滋病的临床特点和发病机制。我们已经阐明了 遗传性ACTH抵抗的分子病理生理学， 常染色体隐性遗传病的特征是孤立的 糖皮质激素缺乏症，通过定义ACTH异常 受体基因我们已经阐明了 睾丸和卵巢对黄体生成素（LH）的抵抗， 定义LH受体基因的异常。我们已经定位了 Carney复合体的两个基因，一种多发性肿瘤/雀斑样痣 综合征，位于染色体2 p16和17 q。我们已经定义了 过度芳香化酶综合征的分子缺陷，一种新的 启动子异常和异位表达， 个体