CRHBP's role in mediating HPA/HPG interactions

CRHBP 在介导 HPA/HPG 相互作用中的作用

• 批准号: 6884256
• 负责人: NICOLE J WESTPHAL
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6884256
• 关键词: SDS polyacrylamide gel electrophoresis; adrenocorticotropic hormone; binding proteins; biological signal transduction; corticotropin releasing factor; crosslink; genetic regulation; genetically modified animals; glycoproteins; gonadotropins; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; hypothalamic pituitary axis; laboratory mouse; pituitary gonadal axis; polymerase chain reaction; predoctoral investigator; protein structure function; site directed mutagenesis; tissue /cell culture; western blottings

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.

描述（由申请人提供）：已知身体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 轴关键的促生长激素减退效应分子，在应激诱导的生殖抑制中发挥着重要作用。虽然已知 CRH 的作用是中枢，但调节作用可能存在于垂体。 CRH 结合两个受体和一个 CRH 结合蛋白 (CRHBP)，这是一种 37kD 的糖蛋白，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激素，这是参与生殖信号传导的主要垂体细胞类型。这种定位和 GnRH 诱导的促性腺激素样细胞中 CRHBP 表达的显着增加表明，应重新检查促性腺激素作为 HPA/HPG 相互作用的潜在位点，并且 CRHBP 可能在调节这些相互作用中发挥重要作用。该提案将研究内源性 CRHBP 表达的 GnRH 调节、介导 GnRH 诱导 CRHBP 基因调节的分子机制，以及促性腺激素中 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 活性对于我们了解涉及 CRH 失调的疾病（包括食欲减退症、焦虑症和生殖障碍）非常重要。