Pathophysiology of The Hypothalamic-pituitary-adrenal & Gonadal Axes

我们试图促进对下丘脑-垂体-肾上腺(HPA)和性腺(HPG)轴的生理学和病理生理学的了解。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。我们已经证明了几种人类状态的特征是中枢应激系统的过度活动或活动不足，这不仅解释了情绪变化，也解释了患有此类疾病的患者发展、代谢、心血管或自身免疫并发症的倾向。我们目前正在对新发现的非肽、口服CRH 1型受体拮抗剂antalarmin进行临床前研究，这些研究表明，这种拮抗剂可能对大量以应激系统过度活动为特征的状态有用，如抑郁、神经性厌食症和特发性失眠。 在应激系统靶组织水平，我们通过定义糖皮质激素受体基因的新突变和/或缺失导致糖皮质激素受体功能异常或受体减少，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，我们描述了炎症诱导的糖皮质激素抵抗和糖皮质激素分泌不足在急性呼吸窘迫综合征中的作用。我们还发现，在中枢神经系统和外周产生昼夜节律的自振荡转录因子CLOCK/BMAL1有节律性地抑制GR诱导的转录活性，表明CLOCK/BMAL1在靶组织中作为糖皮质激素作用的反相负调节因子，可能通过拮抗昼夜波动的循环糖皮质激素的生物作用。此外，在生长停滞细胞中积累的非编码(NC)RNA Gas5，其生理作用尚不清楚，以及腺苷5一磷酸活化蛋白激酶(AMPK)，它是能量稳态的主要调节者，感知体内的能量消耗，刺激增加燃料摄取和节省外周供应的途径，调节GR诱导的转录活性。前者通过充当诱饵RNA GRE来实现这一点，后者通过磷酸化GR来实现这一点。这些结果表明，HPA轴的生物学行为在靶组织水平上受到营养状态和能量来源的调节。 我们已经确定，VPR和TAT是HIV-1的两个小辅助蛋白，是糖皮质激素受体的有效辅助激活因子，可引起明显的靶组织糖皮质激素超敏反应，其存在可能解释了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症的病理生理学和治疗方面也取得了进展，证明了这些患者存在肾上腺素缺乏和胰岛素抵抗，这会导致卵巢功能障碍和代谢异常，同时我们已经证明，雄激素拮抗剂联合芳香酶抑制剂的治疗减少了他们对糖皮质激素治疗的需要，从而获得了更好的身高结果。最后，我们已经证明，21-羟基酶缺乏症的携带者状态是一种常见的情况，与显著的精神和生理发病率有关。最近，我们开始研究线粒体在应激反应中的作用。我们已经建立了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胺氧化酶和氧自由基产生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 (HPA) and -gonadal (HPG) 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 novel 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 also found that CLOCK/BMAL1, the self-oscillating transcription factors that generate circadian rhythms in both the central nervous system and periphery, rhythmically repressed GR-induced transcriptional activity, indicating that CLOCK/BMAL1 functions as a reverse phase negative regulator of glucocorticoid action in target tissues, possibly by antagonizing the biologic actions of diurnally fluctuating circulating glucocorticoids. Furthermore, the noncoding (nc) RNA Gas5, which accumulates in growth-arrested cells, but whose physiologic roles are not known as yet, and the adenosine 5 monophosphate-activated protein kinase (AMPK), a master regulator of energy homeostasis, sensing energy depletion inside the body and stimulating pathways that increase fuel uptake and save on peripheral supplies, regulated GR-induced transcriptional activity. The former accomplished this by acting as a decoy RNA GRE, the latter by phosphorylating the GR. These results indicate that the biologic actions of the HPA axis are regulated at the level of the target tissues by the nutritional state and availability of energy resources. 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 the 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.