PGRMC Proteins as Markers of Fertility and Overall Health Status

项目总结/摘要 有强有力的证据支持卵巢加速老化与不良健康相关的概念 结果。流行病学研究一致报告绝经年龄与 心血管疾病卵巢功能不全（POI）的女性患卵巢功能不全的风险至少增加2倍。 心脏病的风险孕激素受体膜成分（PGRMC）1和PGRMC 2介导 孕酮在雌性生殖组织中的一些抗有丝分裂和抗凋亡作用。尽管是 PGRMC蛋白是一种推测的孕酮受体，在大多数组织中普遍表达， 单细胞真核生物的进化起源。因此，这些蛋白质很可能既有孕酮， 依赖性和非甾体激素依赖性作用。我们的实验室最近将小鼠Pgrmc 1和Pgrmc 2 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 使用Pgr-Cre小鼠的研究表明，Pgrmc 1和Pgrmc 2对女性生育力至关重要， 每个基因的突变导致生育力低下，进而导致过早的生殖衰老。了类似的结果 当PGRMC 1在雌性生殖组织中条件性过表达时观察到。以下条件 每个基因的突变，或PGRMC 1在雌性生殖道中的过度表达， 当Pgrmc基因表达降低或 增加有趣的是，这种衰老的生殖表型伴随着 子宫和卵巢（即，卵巢功能不全（POI）。这种POI样表型反映了患有 PGRMC 1血红素结合域的功能突变。考虑到Pgrmc和 基因突变和生育问题的发展，发展到小鼠不孕症，以及与 人PGRMC基因突变与POI、女性生殖系统癌症和许多其他生殖系统和 在非生殖疾病中，假设PGRMC可用作生育力和总体的标志物。 健康状况。将通过首先评估整个过程中PGRMC 1和PGRMC 2的表达来检验该假设。 12个主要器官的寿命，这些器官调节着健康寿命，并表现出年龄发病性疾病。后果 然后将评估破坏女性生殖组织中PGRMC稳态对整体健康的影响。在这里， PGRMC基因在女性生殖系统中会被选择性地切除或过度表达， 身体组成，健康和细胞衰老参数将在一个全面的评估， 努力将生殖健康与总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.