Pathophysiology of The Hypothalamic-pituitary-adrenal &

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，也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。在同一领域，我们已经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和糖皮质激素分泌不足。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，引起显著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。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。最后，我们已经证明了21-羟化酶缺乏症的载体状态，这是一种常见的疾病，与显著的精神和身体疾病有关。最近，我们开始研究线粒体在应激反应中的作用。我们已经创建了一个人类线粒体基因数据库和微阵列芯片，并确定了糖皮质激素在肌肉细胞单氨基氧化酶和氧自由基生成的调节中的主要输入。

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 described inflammation-induced glucocorticoid resistance and glucocorticoid secretion insufficiency in the acute respiratory distress syndrome. 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. Finally, we have demonstrated that the carrier state of 21-hydroxylase deficiency, a common condition, is associated with significant psychiatric and physical morbidity. Recently we have initiated studies examining the participation of the mitochondria in the stress response. We have created a human mitochondrial gene database and microarray chip and have determined the major input of glucocorticoids in the regulation of the enzyme monoaminoxidase and generation of oxygen radicals in muscle cells.