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，压力也被证明会对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轴的关键垂体营养效应分子，在应激诱导的生殖抑制中起重要作用。虽然已知CRH集中起作用，但调控可能存在于垂体。CRH结合两个受体和一个CRH结合蛋白（CRHBP），一个37kD糖蛋白被认为是CRH活性的重要调节剂。crh受体和CRHBP最近都定位于小鼠促性腺细胞，这是一种参与生殖信号传导的初级垂体细胞类型。这种定位和gnrh诱导的促性腺激素样细胞中CRHBP表达的急剧增加表明，促性腺激素应该作为HPA/HPG相互作用的潜在位点进行重新研究，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GnRH对内源性CRHBP表达的调控，介导GnRH诱导CRHBP基因调控的分子机制，以及CRHBP对促性腺激素中CRH/HPG相互作用的调控。了解生殖激素如何调节CRHBP的表达，以及CRHBP如何调节CRH的活性，对于我们理解涉及CRH失调的疾病，包括抑郁症、厌食症、焦虑和生殖障碍，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.