权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

PGRMC Proteins as Markers of Fertility and Overall Health Status

PGRMC 蛋白作为生育力和整体健康状况的标志

基本信息

批准号：
10729068
负责人：
James K Pru
金额：
$ 39.74万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729068
关键词：
Ablation Acceleration Address Adenomyosis Affect Age Age Months Age Years Age of Onset Aging Antimitotic Agents Apoptotic Binding Body Composition Breast Cardiovascular Diseases Cell Aging Cells Chronic Data Decidual Cell Reactions Development Disease Endometrial Cyst Eukaryota Family Female Female Genital Diseases Female infertility Fertility Fertility Study Gene Expression Gene Mutation Genes Goals Health Health Status Heart Diseases Heme Homeostasis Human Immune System Diseases Incidence Infertility Life Link Literature Longevity LoxP-flanked allele Maintenance Male Infertility Malignant Female Reproductive System Neoplasm Malignant Neoplasms Mediating Membrane Menopause Metabolic Diseases Mus Mutagenesis Mutation National Institute of Child Health and Human Development Onset of illness Organ Outcome Ovarian Ovarian aging Ovary Pathway interactions Phenotype Polycystic Ovary Syndrome Pregnancy loss Premature aging syndrome Progesterone Progesterone Receptors Proteins Pulmonary Heart Disease Recurrence Reporting Reproductive Health Risk Risk Factors Spermatogenesis Subcategory Systems Biology Testing Tissues United States United States National Institutes of Health Uterine Cancer Uterus Woman adverse pregnancy outcome biomarker identification comorbidity endometriosis epidemiology study female fertility female reproductive system frailty gene function healthspan high risk male member men neoplastic novel marker overexpression premature preterm premature rupture of membranes primary ovarian insufficiency reproductive reproductive senescence reproductive system disorder reproductive tract segregation senescence statistics stem subfertility

项目摘要

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.

项目总结/文摘