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）： 不孕不育是美国许多夫妇面临的一个主要问题，是由男性和女性生殖功能障碍引起的。我们的生殖和不孕研究专业合作中心计划 (SCCPIR) 将重点研究多囊卵巢综合征 (PCOS) 女性不孕症和由于精子代谢缺陷导致的男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”，Bruce A. Lessey 医学博士、哲学博士和 Steven A. Young 医学博士、哲学博士将研究子宫对胚胎植入有缺陷的接受性的潜在调节机制。多囊卵巢综合症。尽管成功诱导排卵，多囊卵巢综合症女性的不孕症发病率仍然很高。项目 I 将检验以下假设：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以及类固醇受体和生长因子信号传导紊乱导致相对孕激素抵抗所致。 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 及其辅助调节因子、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，可影响胚胎植入的接受性。在 PCOS 中，MAGE-11 可能会放大 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 NASP 的功能表征”Michael G. O'Rand 博士将与以下机构合作确定 NASP 在性激素受体调节卵巢和子宫内膜基因转录中的作用项目一和二。 NASP 通过影响 H1 组蛋白对染色质重塑的作用而成为细胞周期进程所必需的，而染色质重塑是类固醇受体共调节因子转录调节的关键事件。此外，项目 III 将测试以下假设：NASP 是染色质重塑复合体的一部分，该复合体发出从 G2 到 M 的过渡信号，并修复精子发生中的双链 DNA 断裂。项目 IV，“糖酵解在精子活力和男性生育能力代谢调节中的作用”。 Deborah A. O'Brien 博士通过小鼠精子特异性酶的基因靶向发现，糖酵解可产生运动和生育所需的大部分 ATP。项目 IV 将鉴定维持小鼠和人类精子受精能力的底物，并利用代谢组学策略确定它们的代谢方式。项目一中不孕不育诊所的精子将接受糖酵解缺陷检查，该缺陷是异常运动和不孕的原因。新鉴定的精子特异性糖酵解酶将得到表征，并且将确定获能依赖性磷酸化在糖酵解 ATP 产生中的作用。所有项目的研究均得到行政、细胞分离/组织培养和分子组织学核心以及位于北卡罗来纳大学的国家 SCCPIR 蛋白质组学中心的协助。