Molecular regulation in reproduction

生殖中的分子调控

• 批准号: 7930141
• 负责人: FRANK S FRENCH
• 金额: $ 20.54万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7930141
• 关键词: Molecular; regulation; reproduction

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.

描述（由申请人提供）：不孕是美国许多夫妇的主要问题，是男性和女性生殖功能疾病的结果。我们在多囊卵巢综合征（PCOS）（PCOS）（PCOS）和由于精子中代谢缺陷引起的女性不育症的基础上，我们的专业合作中心计划（SCCPIR研究（SCCPIR）将重点关注女性不孕症的分子机制。项目I，“正常和PCOS子宫内膜中的雌激素作用”，M.D.，博士学位Bruce A. Lessey和M.D.，博士学位的Steven A. Young，将研究对PCOS中胚胎植入的子宫接受性有缺陷的子宫接受性的调节机制。尽管成功排卵诱导，但患有PCOS的女性的不孕症的发生率很高。项目一世将检验以下假设：PCOS中子宫内膜受体的缺陷是由于类固醇受体和生长因子信号传导导致相对孕酮耐药性而导致的雌激素和孕酮作用的不平衡引起的。 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及其核心控剂，黑色素瘤抗原基因产物Mage-11，Mage-11，在人类卵巢中，MAGE-11在granulosa细胞中用AR表达MAGE-11。在子宫内膜中，MAGE-11在分泌早期至中期阶段有选择地表达，它可以影响胚胎植入的接受能力。在PCOS中，MAGE-11可能会扩增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的功能表征”，Michael G. O'Rand博士，将确定NASP在卵巢和子宫内膜在与项目I和II合作中基因转录中NASP在性激素受体调节中的作用。 NASP通过其对H1组蛋白对染色质重塑的作用的影响进行细胞周期进程所必需，这是类固醇受体分支调节转录调节的关键事件。此外，项目III将检验以下假设：NASP是染色质重塑复合物的一部分，该复合物信号是从G2到M的过渡，并修复了精子发生中双链DNA断裂。 IV项目，“糖酵解在精子运动和男性生育能力的代谢调节中的作用”。 Deborah A. O'Brien博士是从糖酵解的小鼠精子特异性酶的基因靶向中发现的，这些酶产生了运动和生育所需的大部分ATP。 IV项目将确定维持小鼠和人类精子中受精能力的底物，并确定它们如何使用代谢组策略来代谢。项目I中的不孕症诊所的精子将检查是否有糖酵解缺陷作为异常运动和不育的原因。将要表征新鉴定的精子特异性糖酵解酶，并将确定依赖性磷酸化在糖酵解ATP产生中的作用。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的帮助，以及位于UNC的国家SCCPIR蛋白质组学中心。