The Primate Corpus Luteum: Functional Regression and Cardiovascular Impacts

项目摘要(参见InstnjcUons)： 该应用程序的长期目标是了解和减少因月经周期结束时灵长类黄体(CL)不适当退化而失去的大量妊娠，并通过确定生殖过程如何影响心血管疾病风险因素，为更好地管理月经周期中的心血管疾病(CVD)风险做出贡献。这项研究计划将解决一个新的假设，即受肝脏x受体(LXR)a和/或p调节的胆固醇摄取和外流活动决定黄体类固醇生成寿命，并降低发生心血管疾病的风险。为了验证这一假设，第一个目的将确定LXR信号是否介导前列腺素F2a(PGF2a)诱导的非灵长类物种黄体溶解。绵羊将在黄体中期接受安慰剂或PGF2a，并采集一系列血液样本，以验证黄体溶解的孕酮(P4)水平降低。将在注射后12、24或48小时收集黄体，并将确定已知LXR目标基因和脂蛋白受体的表达，以及来自新鲜分离组织的细胞培养中胆固醇流出和细胞外脂蛋白摄取的差异。这将验证LXRs介导PGF2a诱导的黄体溶解的假设，并将确定PGF2a诱导的黄体溶解模型在未来研究LXRs在黄体功能中的功能重要性的实用性。第二个具体目标将区分卵巢的直接贡献和全身雌激素(E2)和P4对正常月经周期和荷尔蒙口服避孕药周期中循环脂质的影响。健康的绝经前妇女在正常月经周期内、在卵巢活动暂时停止以模拟更年期后、在诱导绝经期间接受E2和P4替代时以及在单相联合激素口服避孕药周期中，将测定循环血脂水平。这一目标将使我们更好地了解绝经前预防心脏病的潜在机制，并指导未来的研究，以确定生理条件(如衰老、肥胖、糖尿病)和药物干预(如避孕药)如何影响这些绝经前保护因素。

PROJECT SUMMARY (See InstnjcUons): The long-term objectives of this application are to understand and reduce the large numbers of pregnancies that are lost because of inappropriate regression of the primate corpus luteum (CL) at the end of the menstrual cycle, and to contribute to better management of cardiovascular disease (CVD) risk in wromen by determining how reproductive processes influence CVD risk factors. The research plan will address the novel hypothesis that cholesterol uptake and efflux activities, regulated by liver x receptor (LXR) a and/or p,determine luteal steroidogenic lifespan and reduce the risk of developing CVD. To test this hypothesis, the first aim will determine whether LXR signaling mediates prostaglandin F2a (PGF2a)-induced luteolysis in non-primate species. Sheep will receive either placebo or PGF2a during the mid-luteal phase with serial blood samples collected to verify reduced progesterone (P4) levels indicative of luteolysis. Corpora lutea will be collected at 12, 24, or 48 hours after injection and expression of known LXR target genes and lipoprotein receptors will be determined, as well as differences in cholesterol efflux and extracellular lipoprotein uptake in cell cultures derived from freshly isolated tissue. This will test the hypothesis that the LXRs mediate PGF2a-induced luteolysis, and will determine the utility of a PGF2a-induced luteolytic model for future studies on the functional importance of the LXRs in luteal function. The second specific aim will differentiate direct ovarian contributions from systemic estradiol (E2) and P4 effects on circulating lipids during the normal menstrual cycle and hormonal oral contraceptive cycles. Circulating lipid levels will be determined in healthy, premenopausal women during their normal menstrual cycle, after having ovarian activity temporarily stopped to mimic menopause, while receiving E2 and P4 replacement during induced menopause, and during a monophasic combined hormonal oral contraceptive cycle. This aim will better our understanding of the mechanisms underlying premenopausal protection from heart disease and guide future studies to determine how physiologic conditions (e.g. aging, obesity, diabetes) and pharmacologic interventions (e.g. contraceptives) affect these premenopausal protective factors.