Molecular regulation in reproduction

描述（由申请人提供）：不孕症是美国许多夫妇的主要问题，是男性和女性生殖功能障碍的结果。我们的生殖和不孕不育研究专业合作中心计划（SCCPIR）将专注于多囊卵巢综合征（PCOS）女性不孕症和精子代谢缺陷导致的男性不孕症的分子机制。项目I，"雌激素在正常和PCOS子宫内膜中的作用"，布鲁斯A。Lessey，医学博士，博士，和Steven A.杨博士，博士，将研究PCOS患者子宫对胚胎着床的接受性缺陷的调控机制。尽管成功诱导排卵，PCOS妇女不孕症的发生率仍然很高。项目I将检验PCOS患者子宫内膜容受性缺陷的假设，即雌激素和孕激素作用失衡，类固醇受体和生长因子信号紊乱，导致相对孕激素抵抗。 项目II，“雄激素受体（AR）功能的分子决定因素”，伊丽莎白M。威尔逊博士，将确定AR及其辅助调节因子黑色素瘤抗原基因产物法师-11在人卵巢中的作用，其中法师-11与AR一起在颗粒细胞中表达。在子宫内膜中，法师-11选择性地表达于早期至中期分泌期，在此阶段，其可影响胚胎着床的容受性。在PCOS中，法师-11可能放大AR介导的雄激素过多对卵巢和子宫内膜功能的影响。项目III，“H1组蛋白结合蛋白的功能表征，NASP”，Michael G. O'Rand博士，将与项目I和II合作确定NASP在卵巢和子宫内膜性激素受体基因转录调节中的作用。NASP通过其对H1组蛋白对染色质重塑的作用的影响是细胞周期进展所需的，染色质重塑是类固醇受体辅调节因子转录调节中的关键事件。此外，项目III将测试NASP是染色质重塑复合物的一部分的假设，该复合物发出从G2到M的过渡信号并修复精子发生中的双链DNA断裂。项目四，"糖酵解在精子活力和男性生育力的代谢调节中的作用。"Deborah A.奥布莱恩博士，从小鼠精子特异性酶的基因靶向发现，糖酵解产生运动和生育所需的大部分ATP。项目IV将确定维持小鼠和人类精子受精能力的底物，并确定它们如何使用代谢组学策略代谢。项目I中来自不孕症诊所的精子将被检查糖酵解缺陷，糖酵解缺陷是异常运动和不孕症的原因。新发现的精子特异性糖酵解酶的特点和获能依赖磷酸化糖酵解ATP生产的作用将被确定。所有项目的研究都得到了行政、细胞分离/组织培养和分子组织学核心以及位于华盛顿的SCCPIR蛋白质组学国家中心的协助。

DESCRIPTION (provided by applicant): Infertility is a major problem for many couples in the USA and results from disorders of reproductive function in both males and females. Our Specialized Cooperative Centers Program in Reproduction and Infertility Research (SCCPIR) will focus on molecular mechanisms underlying female infertility in polycystic ovarian syndrome (PCOS) and male infertility due to metabolic defects in spermatozoa. Project I, "Estrogen action in normal and PCOS endometrium," Bruce A. Lessey, M.D., Ph.D., and Steven A. Young, M.D., Ph.D., will investigate regulatory mechanisms underlying defective uterine receptivity to embryo implantation in PCOS. A high incidence of infertility persists among women with PCOS despite successful ovulation induction. Project I will test the hypothesis that defective endometrial receptivity in PCOS results from an imbalance in estrogen and progesterone actions with disordered steroid receptor and growth factor signaling causing relative progesterone resistance. Project II, "Molecular determinants of androgen receptor (AR) function," Elizabeth M. Wilson, Ph.D., will determine the role of AR and its coregulator, melanoma antigen gene product, MAGE-11, in the human ovary where MAGE-11 is expressed with AR in granulosa cells. In endometrium MAGE-11 is expressed selectively at the early to mid-secretory stage where it could influence receptivity to embryo implantation. In PCOS, MAGE-11 may amplify AR-mediated effects of androgen excess on ovarian and endometrial functions. Project III, "Functional characterization of the H1 histone binding protein, NASP," Michael G. O'Rand, Ph.D., will determine the role of NASP in sex hormone receptor regulation of gene transcription in the ovary and endometrium in collaboration with Projects I and II. NASP is required for cell cycle progression through its influence on H1 histone action on chromatin remodeling, which is a critical event in steroid receptor coregulator regulation of transcription. In addition, Project III will test the hypothesis that NASP is part of the chromatin remodeling complex that signals the transition from G2 to M and repairs double strand DNA breaks in spermatogenesis. Project IV, "Role of glycolysis in the metabolic regulation of sperm motility and male fertility." Deborah A. O'Brien, Ph.D., discovered from gene targeting of mouse sperm-specific enzymes that glycolysis generates the majority of ATP required for motility and fertility. Project IV will identify substrates that maintain fertilization competence in mouse and human sperm and determine how they are metabolized using metabolomic strategies. Sperm from infertility clinics in Project I will be examined for glycolysis defects as a cause of abnormal motility and infertility. Newly identified sperm-specific glycolytic enzymes will be characterized and the role of capacitation dependent phosphorylation in glycolytic ATP production will be determined. Research for all projects is assisted by Administrative, Cell Separation/Tissue Culture and Molecular Histology Cores and by the National Center for SCCPIR Proteomics located at UNC.