PHYSIOLOGY & PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL & GONADAL AXE

我们寻求推进对下丘脑-垂体-肾上腺轴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多动或低动，这不仅解释了情绪变化，而且解释了患有这种疾病的患者发展心血管或自身免疫性并发症的倾向。我们目前正在对一种新发现的非肽口服CRH 1型受体拮抗剂安他拉明进行临床前研究，该研究表明，这种拮抗剂可能对大量以应激系统过度活跃为特征的状态有用，如抑郁症、神经性厌食症和焦虑症。在应激系统靶组织水平上，我们通过定义糖皮质激素受体基因的突变和/或缺失导致异常功能或受体减少，阐明了糖皮质激素耐药的分子病理生理学。在同一地区，我们发现糖皮质激素受体β显性阴性异构体在糖皮质激素抵抗性哮喘患者中异常表达。最后，我们已经确定Vpr， HIV-1的15kD蛋白产物，是糖皮质激素受体的有效共激活因子，导致靶组织糖皮质激素过敏，其存在可能解释艾滋病的一些临床特征和发病机制。

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 anxiety disorder. 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.