CRHBP's role in mediating HPA/HPG interactions

描述（由申请人提供）：已知生理和心理压力会激活下丘脑-垂体-肾上腺（HPA）轴;然而，压力也会对HP-性腺（HPG）轴产生负面影响。研究表明，促肾上腺皮质激素释放激素（CRH）是HPA轴的关键垂体效应分子，在应激诱导的生殖抑制中起重要作用。虽然CRH是已知的集中行动，调节可能存在于垂体。CRH结合两种受体和CRH结合蛋白（CRHBP），CRHBP是一种37 kD的糖蛋白，被认为是CRH活性的重要调节剂。CRH受体和CRHBP最近已被定位于小鼠促性腺激素细胞，参与生殖信号的主要垂体细胞类型。这种定位和显着的促性腺激素释放激素诱导的CRHBP在促性腺激素样细胞中的表达增加表明，促性腺激素应重新检查HPA/HPG相互作用的潜在网站，CRHBP可能在调节这些相互作用中发挥重要作用。本研究将探讨促性腺激素释放激素对内源性CRHBP表达的调控，促性腺激素释放激素诱导CRHBP基因调控的分子机制，以及促性腺激素细胞中CRH/HPG相互作用的CRHBP调节。了解生殖激素如何调节CRHBP表达以及CRHBP如何调节CRH活性对于我们理解涉及CRH失调的疾病（包括抑郁性厌食症、焦虑症和生殖障碍）将是重要的。

DESCRIPTION (provided by applicant): Physical and psychological stress are known to activate the hypothalamic-pituitary-adrenal (HPA) axis; however, stress has also been shown to negatively impact the HP-gonadal (HPG) axis. Studies have demonstrated that Corticotropin-Releasing Hormone (CRH), the key hypophysiotrophic effector molecule of the HPA axis, plays a significant role in stress-induced inhibition of reproduction. While CRH is known to act centrally, regulation may exist at the pituitary. CRH binds two receptors and a CRH binding protein (CRHBP), a 37kD glycoprotein thought to be an important modulator of CRH activity. Both CRH-receptors and CRHBP have recently been localized to murine gonadotrope, the primary pituitary cell type involved in reproductive signaling. This localization and the dramatic GnRH-induced increases in CRHBP expression in gonadotrope-like cells suggest that the gonadotrope should be reexamined as a potential site for HPA/HPG interactions and that CRHBP may play an important role in modulating these interactions. This proposal will examine GnRH regulation of endogenous CRHBP expression, molecular mechanisms mediating GnRH induced CRHBP gene regulation, and CRHBP modulation of CRH/HPG interactions in gonadotrope. An understanding of how reproductive hormones regulate CRHBP expression and how CRHBP modulates CRH activity will be important for our understanding of diseases involving CRH dysregulation, including deoression anorexia, anxiety and reproductive disorders.