INTRACELLULAR MECHANISMS REGULATING LH SUBUNIT

LH 亚基的细胞内调节机制

• 批准号: 3323955
• 负责人: John C Marshall
• 金额: $ 12.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1993-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3323955
• 关键词: calcium; complementary DNA; cyclic AMP; cyclic GMP; estradiol; gene expression; genetic transcription; gonadotropin releasing factor; hormone analog; hormone receptor; hormone regulation /control mechanism; laboratory rabbit; laboratory rat; luteinizing hormone; messenger RNA; peptide hormone biosynthesis; perfusion; phosphatidylinositols; progesterone; prolactin; protein kinase C; receptor sensitivity; testosterone; triiodothyronine

The aim of experiments in this proposal is to elucidate the intracellular mechanisms (2nd messengers) by which gonadotropin- releasing hormone (GnRH) stimulates expression of the alpha and LH beta subunit mRNAs required for LH synthesis by pituitary gonadotrope cells. The studies will be performed in vitro and physiologic pulses of GnRH used to stimulate pituitary gonadotropes. Gonadotrope responses will be assessed by measurement of GnRH receptors, alpha and LH beta mRNA concentration, LH storage and acute release. The effect of prolactin and gonadal steroids on cellular responses to GnRH will be determined. The intracellular mechanisms involved in transmitting the GnRH signal to stimulate LH subunit gene expression will be examined by measurement of mRNA responses to agents which bypass the GnRH receptor. The effects of both continuous and pulsatile elevation of intracellular calcium and cyclic nucleotides, and constant or intermittent stimulation of protein kinase C on LH subunit mRNA concentrations will be determined. By comparison of the effects of these stimuli with those following GnRH pulses, we aim to elucidate the intracellular mechanism(s) involved in transmission of the signal initiated by GnRH-receptor binding. Subsequent studies will examine if gonadal steroids regulate GnRH action by modifying LH subunit mRNA responses to the second messengers. Other studies will examine the mechanisms involved in desensitization of LH secretion by a continuous GnRH stimulus. The role of mRNA expression and the ability of GnRH to stimulate phosphoinositol hydrolysis in desensitized cells will be examined. The mechanisms of GnRH action have important implications for the regulation of fertility in humans and animals. A pulsatile GnRH stimulus is required to maintain LH secretion and continuous stimulation by GnRH desensitizes LH secretion. Specific syndromes of GnRH deficiency are recognized in humans and fertility can be restored by administration of GnRH in a pulsatile manner. Long acting GnRH agonists which desensitize LH release are being assessed as potential contraceptive agents. The elucidation of the exact mechanisms by which a pulsatile GnRH stimulus maintain LH synthesis and secretion are important for the development of future therapeutic regimens to both enhance or inhibit gonadotropin secretion.

本提案中的实验目的是阐明 细胞内机制（第二信使），促性腺激素- 释放激素（GnRH）刺激α的表达， 垂体合成LH所需的LH β亚单位mRNA 促性腺细胞 研究将在体外进行， 用于刺激垂体的GnRH生理脉冲 促性腺激素 促性腺激素反应将通过以下指标进行评估： GnRH受体α和LH β mRNA的测量 浓度、LH储存和急性释放。 的影响 催乳素和性腺类固醇对GnRH细胞反应的影响将 被确定。 参与的细胞内机制 传递GnRH信号刺激LH亚单位基因 将通过测量mRNA反应来检查表达 绕过GnRH受体的药物。 的效果 细胞内钙离子的持续和脉动性升高， 环核苷酸，以及持续或间歇刺激 蛋白激酶C对LH亚单位mRNA浓度的影响 测定 通过比较这些刺激的效果， 在GnRH脉冲后，我们的目标是阐明 参与信号传递的细胞内机制 由GnRH受体结合引发。 后续研究将 检查性腺类固醇是否通过改变 LH亚单位mRNA对第二信使的反应。 其他 研究将检查脱敏的机制 促性腺激素释放激素的持续刺激。 的作用 mRNA表达和GnRH刺激的能力 将检测脱敏细胞中的磷酸肌醇水解。 GnRH的作用机制对以下方面具有重要意义： 调节人类和动物的生育能力。 脉动 需要GnRH刺激来维持LH分泌， GnRH的持续刺激使LH分泌脱敏。 GnRH缺乏症的特定综合征在人类中被识别 和生育能力可以恢复管理的GnRH在一个 搏动的方式。 脱敏的长效GnRH激动剂 LH释放被评估为潜在的避孕药。 阐明了一种脉动性心脏病 促性腺激素释放激素（GnRH）刺激对LH的合成和分泌起重要作用 用于开发未来的治疗方案， 增强或抑制促性腺激素分泌。