Pathophysiology of Hypothalamic-Pituitary-Adrenal Axis

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发育、代谢心血管或自身免疫性并发症的倾向。我们目前正在对新发现的非肽口服CRH 1型受体拮抗剂安他拉明进行临床前研究，结果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、神经性厌食症和特发性失眠。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，阐明了散发性和家族性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哮喘患者中异常表达，并描述了急性呼吸窘迫综合征中炎症诱导的糖皮质激素抵抗。最后，我们已经确定Vpr和Tat，两个小的HIV-1辅助蛋白，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。此外，我们在了解先天性肾上腺增生的病理生理和治疗方面取得了进展，通过证明这些患者有肾上腺素缺乏和胰岛素抵抗，导致卵巢功能障碍和代谢异常，而我们已经证明雄激素拮抗剂联合芳香化酶抑制剂治疗减少了他们对糖皮质激素治疗的需求，从而获得更好的身高结果。

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 developmental, metabolic cardiovascular or autoimmune complications. We are currently performing preclinical studies with the 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 sporadic and familial 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, and have described inflammation-induced glucocorticoid resistance in the acute respiratory distress syndrome. Finally, we have determined that Vpr and Tat, two small HIV-1 accessory proteins, are potent coactivators 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. Also, we have made advances in understanding the pathophysiology and treatment of congenital adrenal hyperplasia, by demonstrating that these patients have epinephrine deficiency and insulin resistance, which leads to ovarian dysfunction and metabolic abnormalities, while we have shown that treatment with androgen antagonists combined with aromatase inhibitors decreases their need for glucocorticoid therapy resulting in a better height outcome.