PGRMC Proteins as Markers of Fertility and Overall Health Status

项目总结/文摘

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.