Pathophysiology of the Hypothalamic-pituitary-adrenal &

下丘脑-垂体-肾上腺的病理生理学

• 批准号: 6541135
• 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/6541135
• 关键词: anorexia nervosa; autoimmune disorder; clinical research; corticosteroid receptors; corticotropin releasing factor; depression; hormone regulation /control mechanism; human subject; hypothalamic pituitary adrenal axis; mood disorders; neuropathology; neurophysiology; pituitary gonadal axis; sleep disorders; stress

We seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary-adrenal and -gonadal axes. The roles of the stress-related hormones corticotropin-releasing hormone (CRH) and glucocorticoids in normal and disease states are being examined, and clinical applications for these hormones and their antagonists are sought. We have demonstrated that several human states are characterized by hyperactivity or hypoactivity of the central stress system, which explains not only mood changes but also the propensity of patients with such disorders to develop cardiovascular or autoimmune complications. We are currently performing preclinical studies with a newly discovered nonpeptide, oral, CRH type 1 receptor antagonist, antalarmin, which show that such an antagonist may be useful in a large number of states characterized by hyperactivity of the stress system, such as depression, anorexia nervosa and idiopathic insomnia. At the level of the stress system target tissues, we have elucidated the molecular pathophysiology of glucocorticoid resistance by defining mutations and/or deletions of the glucocorticoid receptor gene leading to abnormally functioning or decreased receptors. In the same area,we have found abnormal expression of the beta dominant negative isoform of the glucocorticoid receptor in patients with glucocorticoid resistant asthma. Finally, we have determined that Vpr, a 15kD protein product of HIV-1, is a potent coactivator of the glucocorticoid receptor, causing marked target tissue glucocorticoid hypersensitivity, the presence of which may explain some of the clinical features and pathogenesis of AIDS.

我们寻求推进下丘脑-垂体-肾上腺和性腺轴的生理学和病理生理学的理解。应激相关激素促肾上腺皮质激素释放激素（CRH）和糖皮质激素在正常和疾病状态下的作用正在研究中，并寻求这些激素及其拮抗剂的临床应用。我们已经证明，几种人类状态的特征是中枢应激系统的活动过度或活动减退，这不仅解释了情绪变化，而且还解释了患有此类疾病的患者发生心血管或自身免疫并发症的倾向。我们目前正在进行临床前研究与新发现的非肽类，口服，CRH 1型受体拮抗剂，antalarmin，这表明，这样的拮抗剂可能是有用的，在大量的状态下，其特征在于过度活跃的应激系统，如抑郁症，神经性厌食症和特发性失眠。在应激系统靶组织的水平上，我们通过定义糖皮质激素受体基因的突变和/或缺失导致受体功能异常或减少来阐明糖皮质激素抵抗的分子病理生理学。在同一区域，我们发现糖皮质激素抵抗性哮喘患者糖皮质激素受体β显性阴性亚型表达异常。最后，我们已经确定Vpr，HIV-1的15 kD蛋白产物，是糖皮质激素受体的有效共激活剂，引起明显的靶组织糖皮质激素超敏反应，其存在可能解释艾滋病的一些临床特征和发病机制。