The Primate Corpus Luteum: Functional Regression and Cardiovascular Impacts

项目总结（见说明）： 本申请的长期目标是了解和减少大量的妊娠丢失，因为不适当的退化灵长类动物黄体（CL）在月经周期结束时，并有助于更好地管理心血管疾病（CVD）的风险，在妇女通过确定如何生殖过程影响CVD的危险因素。该研究计划将解决新的假设，即由肝脏x受体（LXR）a和/或p调节的胆固醇摄取和流出活动决定黄体类固醇生成寿命并降低发生CVD的风险。为了检验这一假设，第一个目标将确定LXR信号传导是否介导非灵长类物种中前列腺素F2 a（PGF 2a）诱导的黄体溶解。绵羊将在黄体中期接受安慰剂或PGF 2a，采集系列血样以验证表明黄体溶解的孕酮（P4）水平降低。将在注射后12、24或48小时采集黄体，并测定已知LXR靶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物中胆固醇流出和细胞外脂蛋白摄取的差异。这将检验LXR介导PGF 2a诱导的黄体溶解的假设，并将确定PGF 2a诱导的黄体溶解模型对于LXR在黄体功能中的功能重要性的未来研究的实用性。第二个具体目标是区分正常月经周期和激素口服避孕药周期中卵巢对循环脂质的直接贡献与全身雌二醇（E2）和P4的影响。将在健康的绝经前女性的正常月经周期、卵巢活动暂时停止以模拟绝经后、诱导绝经期间接受E2和P4替代以及双相联合激素口服避孕药周期期间测定循环脂质水平。这一目标将使我们更好地了解绝经前心脏病保护的机制，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的保护因素。

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.