ACTIONS OF ESTROGEN IN MATURING GRAAFIAN FOLLICLES

描述(改编自调查人员摘要)：这是一个修改后的 竞争更新申请，以调查控制机制 发育中的Graafian卵泡中的类固醇生成。私家侦探已经 发现了两个关键基因的协同激素调节 对于固醇代谢，即低密度脂蛋白(LDL)受体和 类固醇合成急性调节蛋白(STAR)。这两个在功能上 互补基因对于调节卵巢类固醇激素的生成至关重要，因为 低密度脂蛋白受体是传递细胞外信号的主要通道 胆固醇进入颗粒黄体细胞，而STAR充当 限速转运蛋白将类固醇底物输送到内层 线粒体胆固醇侧链裂解酶复合体。私家侦探已经 发现促性腺激素、卵泡刺激素(FSH)和 卵泡内生长因子、胰岛素样生长因子-1共同作用 产生8-20倍的协同刺激，以增强 低密度脂蛋白受体和STAR基因的表达。这项提议涉及到 这种协同作用的机制。具体的假设是 研究结果如下：1)低密度脂蛋白受体和STAR基因协同表达 随着时间的推移，猪发情周期；2)FSH和IGF-1协同作用 通过扩增刺激增加的低密度脂蛋白受体和STAR mRNA的表达 蛋白激酶A的胞内信号通路；3)FSH和IGF-1 诱导单个颗粒低密度脂蛋白受体和STAR基因的表达 通过放大每个基因转录本的量在细胞水平上 颗粒细胞和/或通过增加表达颗粒细胞的数量 可测量的固醇调节基因转录本；4)FSH和IGF-1增加 特异性低密度脂蛋白受体和STAR基因转录起始率 减少特定的信使核糖核酸降解(或两者兼而有之)。这些研究预计将 揭示了一种脑垂体激素(FSH)和 生长因子(IGF-1)单独或协同作用于卵巢细胞 种群和单个类固醇合成颗粒细胞来控制 关键基因的协同表达和协同扩增 直接全面类固醇生成。

DESCRIPTION (Adapted from the Investigator's Abstract): This is an amended competing renewal application to investigate the mechanisms controlling steroidogenesis within developing Graafian follicles. The P.I. has discovered synergistic hormonal regulation of two critical genes responsible for sterol metabolism, namely, low density lipoprotein (LDL) receptor and steroidogenic acute regulatory protein (StAR). These two functionally complementary genes are critical to regulated ovarian steroidogenesis, since the LDL receptor serves as the primary gateway for delivering extracellular cholesterol into the granulosa-luteal cell, and StAR acts as the rate-limiting transporter protein to convey sterol substrate to the inner mitochondrial cholesterol side-chain cleavage enzyme complex. The P.I. has found that the gonadotropin, follicle stimulating hormone (FSH), and the intrafollicular growth factor, insulin like growth factor 1 (IGF-1) together produce a synergistic stimulation of 8-20 fold in the enhancement of expression of LDL receptor and StAR mRNA. This proposal concerns the mechanisms of this synergistic action. The specific hypotheses to be investigated are: 1) LDL-receptor and StAR genes are expressed coordinately over time throughout the pig estrous cycle; 2) FSH and IGF-1 synergistically stimulate increased LDL receptor and StAR mRNA expression via amplification of the protein kinase A intracellular signaling pathway; 3) FSH and IGF-1 induce expression of LDL receptor and StAR genes at the single granulosa cell level by amplifying the amount of each gene transcript expressed per granulosa cell and/or by increasing the number of granulosa cells expressing measurable sterol-regulatory gene transcripts; 4) FSH and IGF-1 increase specific LDL-receptor and StAR gene transcriptional initiation rates or decrease specific mRNA degradation (or both). These studies are expected to reveal fundamental mechanisms by which a pituitary hormone (FSH) and the growth factor (IGF-1) act either alone or in concert on ovarian cell populations and on single steroidogenic granulosa cells to control the coordinated expression and synergistic amplification of pivotal genes that direct overall steroidogenesis.