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.

U54HD035041

1997-04-07

2014-03-31