REGULATION OF THE CORPUS LUTEUM

这项资助的总体目标是定义生理和细胞 灵长类黄体退化的机制 终止不孕月经周期以及理解 黄体寿命延长的机制 在怀孕早期。我们之前的调查结果是 表明在黄体中期有一个关键期 月经周期，其特征是对月经周期的依赖性增强 黄体在黄体黄体上。目前提案的总体目标是 阐明致病机制和细胞相关因素 用食蟹猴降低黄体对黄体生成素的敏感性 猕猴作为实验模型。 在特定的目标1中，我们将使用体内和体外的组合 直接评估细胞内信号系统的程序 黄体年龄决定子宫内膜反应性是否发生改变 蛋白激酶A和/或蛋白激酶C通路改变为 黄体年龄。在这一具体目标中包括研究，以确定 如果PKA和PKC信号系统不同地调节 参与黄体合成类固醇的mRNAs的表达 以及这些信号系统对RNA表达的影响是否 由于转录和/或RNA稳定性的变化。在具体目标2中， 我们将继续我们的初步调查结果，似乎有重大的 核转录因子表达的变化 伴随黄体黄体化和黄体老化。特别是，我们 将确定黄体是否表达CREB的变种形式 使这个主要的转录因子失去活性。我们还将调查 受基因调控的其他转录因子表达 PKA和PKC信号系统判断是否存在年龄依赖性 这些蛋白质在黄体中表达的变化。在……里面 具体目标3，我们将检验生理信号的假设 在怀孕早期挽救黄体是一种开关 从脉冲性促性腺激素分泌到持续暴露体部 黄体到促性腺激素。在最终的具体目标中，我们将确定是否 人脑小体分泌血管内皮生长因子的研究 黄体是在促性腺激素的控制下，这种分泌 血管生成蛋白随着黄体期的进展而减少。 除了提供重要的基本信息外， 灵长类动物黄体的功能，这里提出的研究可以 提供有关改变的病理生理学的新信息 人类黄体的功能，如短的黄体期 以及黄体期不足，这两个因素都被认为是 不孕不育和早期妊娠损失。此外，我们还研究了 血管内皮生长因子可能会透露出有关危及生命的原因的新信息 严重卵巢疾病时体液平衡的变化 过度刺激综合症。

The overall goal of this grant is to define the physiological and cellular mechanisms responsible for the regression of the primate corpus luteum at the termination of the nonfertile menstrual cycle as well as to understand the mechanisms by which the lifespan of the corpus luteum is prolonged during early pregnancy. Results of our previous investigations have indicated that there is a critical period during the midluteal phase of the menstrual cycle that is characterized by heightened dependency of the corpus luteum upon LH. The overall goal of the current proposal is to elucidate the mechanisms and cellular correlates responsible for the diminished sensitivity of the corpus luteum to LH, using the cynomolgus macaque as an experimental model. In Specific Aim 1, we will use a combination of in vivo and in vitro procedures to directly assess the intracellular signaling systems as a function of luteal age to determine if changes in the responsiveness of protein kinase A and/or protein kinase C pathways are altered as the corpus luteum ages. Included in this Specific Aim are studies to determine if the PKA and PKC signaling systems differentially regulate the expression of mRNAs involved in steroid production by the corpus luteum and whether the effects of these signaling systems on RNA expression are due to changes in transcription and/or RNA stability. In Specific Aim 2, we will pursue our preliminary finding that there appear to be major alterations in the expression of nuclear transcription factors that accompany luteinization and aging of the corpus luteum. In particular, we will determine if the corpus luteum expresses a variant form of CREB that renders this major transcription factor inactive. We will also investigate the expression of other transcription factors that are regulated by the PKA and PKC signaling systems to determine if there are age-dependent alterations in the expression of these proteins in the corpus luteum. In Specific Aim 3, we will test the hypothesis that the physiological signal by which the corpus luteum is rescued during early pregnancy is a switch from pulsatile gonadotropin secretion to continuous exposure of the corpus luteum to gonadotropin. In the final Specific Aim, we will determine if the secretion of vascular endothelial growth factor (VEGF) by the corpus luteum is under gonadotropic control and whether the secretion of this angiogenic protein diminishes as the luteal phase progresses. In addition to providing important basic information regarding the functioning of the primate corpus luteum, the studies proposed herein may provide novel information regarding the pathophysiology of altered functioning of the corpus luteum in humans such as the short lutel phase and the inadequate luteal phase, both of which are thought to contribute to infertility and early gestational losses. In addition, our studies on VEGF may shed new information regarding the cause of the life-threatening changes in body fluid homeostasis that accompanies severe ovarian hyperstimulation syndrome.