REGULATION OF THE CORPUS LUTEUM

这项资助的总体目标是确定生理和细胞 灵长类动物黄体退化的机制 不孕月经周期的终止以及了解 黄体寿命延长的机制 在怀孕早期。我们之前的调查结果 表明，在黄体中期有一个关键时期， 月经周期的特点是高度依赖于 黄体分泌本提案的总体目标是 阐明机制和细胞相关负责 降低黄体对LH的敏感性，使用食蟹猴 猕猴作为实验模型。 在具体目标1中，我们将结合使用体内和体外 直接评估细胞内信号系统的程序， 功能的黄体年龄，以确定是否变化的反应， 蛋白激酶A和/或蛋白激酶C途径被改变， 黄体老化。本具体目标中包括的研究旨在确定 如果PKA和PKC信号系统差异调节 参与黄体产生类固醇的mRNA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， 我们将继续调查初步结果， 核转录因子表达的改变， 伴随黄体化和黄体老化。我们尤其 将确定黄体是否表达CREB的变体形式， 使该主要转录因子失活。我们亦会研究 其他转录因子的表达，这些转录因子由 PKA和PKC信号系统，以确定是否有年龄依赖性 黄体中这些蛋白质表达的改变。在 具体目标3，我们将测试生理信号 在怀孕早期挽救黄体的方法是一个开关， 从脉冲性促性腺激素分泌到持续暴露于 黄体到促性腺激素。在最后的具体目标中，我们将确定 体分泌血管内皮生长因子（VEGF） 黄体是在促性腺激素的控制下，这种分泌是否 血管生成蛋白随着黄体期进展而减少。 除了提供有关 灵长类动物黄体的功能，本文提出的研究可能 提供了新的信息，关于改变的病理生理学 人类黄体的功能，如短黄体期 以及黄体期不足，这两者都被认为是导致 不孕症和早期妊娠丢失。此外，我们对 VEGF可能会提供有关危及生命的疾病原因的新信息。 伴随重度卵巢癌的体液稳态变化 过度刺激综合征

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.