Molecular regulation in reproduction

描述（由申请人提供）：不孕不育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。我们的生殖与不孕症研究专业合作中心项目（SCCPIR）将专注于多囊卵巢综合征（PCOS）女性不育和精子代谢缺陷导致的男性不育的分子机制。项目一，“雌激素在正常和多囊卵巢综合征子宫内膜中的作用”，Bruce A. Lessey医学博士和Steven A. Young医学博士将研究多囊卵巢综合征患者子宫容受性缺陷对胚胎着床的调节机制。尽管成功诱导排卵，多囊卵巢综合征妇女不孕的发生率仍然很高。项目1将检验PCOS患者子宫内膜容受性缺陷是由于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的假设。项目II，“雄激素受体（AR）功能的分子决定因素”，Elizabeth M. Wilson博士将确定AR及其协同调节因子，黑色素瘤抗原基因产物MAGE-11在人类卵巢中的作用，其中MAGE-11在颗粒细胞中与AR一起表达。在子宫内膜中，MAGE-11在分泌早期至中期选择性表达，影响胚胎着床的接受性。在多囊卵巢综合征中，MAGE-11可能会放大ar介导的雄激素过量对卵巢和子宫内膜功能的影响。项目III，“H1组蛋白结合蛋白NASP的功能特征”，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。通过影响H1组蛋白对染色质重塑的作用，NASP是细胞周期进程所必需的，这是类固醇受体协同调节转录的关键事件。此外，项目III将验证NASP是染色质重塑复合体的一部分的假设，该复合体标志着从G2到M的转变，并修复精子发生过程中的双链DNA断裂。项目四，“糖酵解在精子活力和男性生育能力的代谢调节中的作用”。Deborah A. O'Brien博士从小鼠精子特异性酶的基因靶向中发现，糖酵解产生了运动和生育所需的大部分ATP。项目四将确定维持小鼠和人类精子受精能力的底物，并确定它们是如何使用代谢组学策略代谢的。项目一不孕不育诊所的精子将被检查是否存在糖酵解缺陷，因为糖酵解缺陷是运动异常和不孕的原因。新发现的精子特异性糖酵解酶将被表征，并确定磷酸化在糖酵解ATP生产中的作用。所有项目的研究都由行政，细胞分离/组织培养和分子组织学核心以及位于UNC的SCCPIR蛋白质组学国家中心协助。

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.