PGRMC Proteins as Markers of Fertility and Overall Health Status

项目摘要/摘要 有强有力的证据支持这样一个概念，即卵巢老化加速与健康不良有关 结果。流行病学研究一致地报告绝经年龄和 心血管疾病。患有卵巢功能不全(POI)的女性风险至少增加2倍 罹患心脏病的风险。孕激素受体膜组分(PGRMC)1和PGRMC2介导 黄体酮在女性生殖组织中的一些抗有丝分裂和抗凋亡作用。尽管 作为一种所谓的孕激素受体，PGRMC蛋白在大多数组织中普遍表达，并具有 单细胞真核生物的进化起源。因此，这些蛋白质很可能同时含有黄体酮- 依赖和黄体酮非依赖性的作用。我们实验室最近用牙线剔除了小鼠PGRMC1和Pgrmc2 基因，以评估这些基因在女性生育能力方面的功能。诱变研究 对PGR-CRE小鼠的研究表明，在条件消融中，PGRMC1和Pgrmc2对女性生育是必不可少的 每一种基因的缺失都会导致不育症，进而导致过早的生殖衰老。类似的结果是 观察到PGRMC1在女性生殖组织中有条件地过度表达。以下条件 每个基因的突变，或PGRMC1在女性生殖道的过度表达，早产儿 当Pgrmc基因表达降低或 增加了。有趣的是，这种衰老的生殖表型伴随着 子宫和卵巢(即卵巢早衰，POI)。这种类似POI的表型反映了患有 PGRMC1的血红素结合区的功能突变。给定Pgrmc与Pgrmc之间的因果关系 基因突变与进展为小鼠不孕症的生育问题及其关联 人类PGRMC基因突变与POI、女性生殖道癌和许多其他生殖和 非生殖性疾病，推测PGRMCs可以作为生育和总体的标志 健康状况。这一假设将通过首先评估整个过程中PGRMC1和PGRMC2的表达来检验 12个调节健康的主要器官的寿命延长，并出现老年性疾病。后果是什么？ 然后将评估破坏女性生殖组织中PGRMC动态平衡对整体健康的影响。这里, PGRMC基因将在女性生殖系统中选择性地被消融或过度表达，然后变得脆弱， 身体成分、健康寿命和细胞衰老参数将在 努力将生殖健康与整体健康直接联系起来。

Project Summary/Abstract Strong evidence exists to support the concept that accelerated ovarian aging associates with adverse health outcomes. Epidemiological studies consistently report an association between age at menopause and cardiovascular disease. Women with premature ovarian insufficiency (POI) have at least a 2-fold increased risk of developing heart disease. Progesterone receptor membrane component (PGRMC) 1 and PGRMC2 mediate some of the anti-mitotic and anti-apoptotic actions of progesterone in female reproductive tissues. Despite being a purported progesterone receptor, PGRMC proteins are ubiquitously expressed in most tissues and have their evolutionary origin in single celled eukaryotes. As such, it is likely that these proteins have both progesterone- dependent and progesterone-independent actions. Our lab recently floxed the murine Pgrmc1 and Pgrmc2 genes in an effort to evaluate the function of these genes in the context of female fertility. Mutagenesis studies using Pgr-Cre mice revealed that Pgrmc1 and Pgrmc2 are essential for female fertility in that conditional ablation of each gene results in subfertility that progresses to premature reproductive senescence. Similar results were observed when PGRMC1 is conditionally over-expressed in female reproductive tissues. Following conditional mutagenesis of each gene, or over-expression of PGRMC1 in the female reproductive tract, a premature reproductive senescence phenotype occurred when the expression of Pgrmc genes was decreased or increased. Interestingly, this senescent reproductive phenotype was accompanied by premature aging of the uterus and ovary (i.e., premature ovarian insufficiency, POI). This POI-like phenotype mirrors that of women with a functional mutation in the heme binding domain of PGRMC1. Given the causal relationship between Pgrmc gene mutations and development of fertility issues that advance to infertility in mice, as well as the association of human PGRMC gene mutations with POI, female reproductive cancers, and many other reproductive and non-reproductive diseases, it is hypothesized that PGRMCs can be used as markers of fertility and overall health status. This hypothesis will be tested by first evaluating expression of PGRMC1 and PGRMC2 throughout the lifespan in 12 major organs that regulate healthspan and present with age-onset disease. The consequences of disrupting PGRMC homeostasis in female reproductive tissues on overall health will then be evaluated. Here, PGRMC genes will be selectively ablated or over-expressed in the female reproductive system and then frailty, body composition, healthspan and cellular senescence parameters will be comprehensively evaluated in an effort to directly link reproductive health to overall health.