Regulation and function of Egr in gonadotropes.

促性腺激素中 EGR 的调节和功能。

• 批准号: 7017690
• 负责人: MICHAEL W WOLFE
• 金额: $ 31.58万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017690
• 关键词: adenylate cyclase; biological signal transduction; gene expression; gene induction /repression; genetic promoter element; genetic regulation; genetically modified animals; gonadotropin releasing factor; immunoprecipitation; laboratory mouse; luteinizing hormone; neuropeptides; protein protein interaction; transcription factor; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): Luteinizing hormone (LH) is synthesized and secreted by gonadotropes within the anterior pituitary gland and is composed of an alpha- and LHbeta-subunit. Expression of these subunits and secretion of LH is exquisitely controlled by the hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH). Absence of GnRH in humans (Kallmann's syndrome) results in complete failure of reproduction due to a lack of gonadotropins. Polycystic ovarian syndrome is characterized by elevated plasma LH and abnormal ovarian function. Therefore, appropriate secretion of LH and thus, expression of LHbeta is critical for maintenance of reproductive function. The goal of the present proposal is to delineate the mechanisms responsible for GnRH regulation of the LHbeta-subunit gene. It is hypothesized that the immediate-early gene product, early growth response protein-I (Egrl), is critical for relaying the GnRH stimulus to the LH beta promoter. Furthermore, it is postulated that Egrl binds to the LHbeta promoter and forms interactions with adjacent transcription factors and transcriptional coactivators/corepressors. Egrl is known to interact with the corepressors Nab1 and 2 and this may modulate Egrl-dependent gene regulation. The goal of Aim I is to elucidate the mechanisms by which GnRH is able to augment the transcriptional activity of Egrl and subsequently enhance expression of the LHbeta promoter. The studies proposed in Aim II will evaluate the mechanisms used by pituitary adenylate cyclase-activating polypeptide to regulate Egrl activity specifically focusing on changes in protein-protein interactions. Finally, the involvement of Nab in vivo in modulating GnRH/Egrl induction of LHbeta will be examined in Aim III using a cre/IoxP conditional expression model. These aims are designed to reveal the molecular mechanisms responsible for GnRH induction of the LHbeta-subunit gene. They intentionally focus on the role played by Egrl due to its essential function in vivo in regulating and maintaining LHp expression. Information obtained from these experiments will provide valuable insights into why GnRH induction of LHbeta expression is intimately tied to a specific pattern of pulsatile release of GnRH from the hypothalamus.

性状（由申请人提供）：促黄体生成素（LH）由垂体前叶内的促性腺激素合成和分泌，由α亚基和LH β亚基组成。这些亚单位的表达和LH的分泌受下丘脑神经肽促性腺激素释放激素（GnRH）的精细控制。人类缺乏GnRH（卡尔曼综合征）会由于缺乏促性腺激素而导致生殖完全失败。多囊卵巢综合征的特征是血浆LH升高和卵巢功能异常。因此，LH的适当分泌以及LH β的表达对于维持生殖功能至关重要。本研究的目的是阐明GnRH调节LH β亚基基因的机制。据推测，即早期基因产物，早期生长反应蛋白-I（Egrl），是关键的中继GnRH刺激LH β启动子。此外，推测Egrl结合LH β启动子并与相邻的转录因子和转录辅激活因子/辅抑制因子形成相互作用。已知Egr 1与辅阻遏物Nab 1和Nab 2相互作用，这可能调节Egr 1依赖的基因调控。目的I的目的是阐明GnRH能够增强Egrl的转录活性并随后增强LH β启动子表达的机制。目的II中提出的研究将评估垂体腺苷酸环化酶激活多肽用于调节Egrl活性的机制，特别关注蛋白质-蛋白质相互作用的变化。最后，将在Aim III中使用cre/IoxP条件表达模型检查Nab在体内参与调节LH β的GnRH/Egrl诱导。这些目的旨在揭示LH β亚基基因的GnRH诱导的分子机制。由于Egrl在体内调节和维持LHp表达的基本功能，他们有意关注Egrl所发挥的作用。从这些实验中获得的信息将提供有价值的见解，为什么GnRH诱导LH β表达密切相关的特定模式的脉冲式释放的GnRH从下丘脑。