The human population continues to expand alarming rates making the development of safer, more economical and effective contraceptives an important health-related goal. In a 1997 survey by the Henry J. Kaiser Family Foundation, more than 66% of respondents believed that men should play a larger role in contraceptive use. The ability to intervene in fertilization could aid couples wanting children, increase reproductive efficiency in endangered species or domestic animals used as food sources, and decrease fertilization rates of certain wild animal populations such as vermin, benefiting the health of millions of people. However, the fertilization process remains poorly understood, leading to severe limitations in development of methods to intervene. The over-all goal of this project is to identify genes critical to sperm behavior and fertilization. The criterion for initial selection of genes relies on cDNA sequences encoding proteins that predict a sperm receptor, channel, transporter, adhesion protein, translocase or ion exchanger, and on genes expressed exclusively in spermatozoa during or after meiosis.
Specific Aim 1 centers on the discovery and functional analysis of new sperm candidate genes (lectin-like, single TM potential receptor, chemokine-like tetraspan). They will be targeted for disruption to determine the effects on sperm behavior and fertility. The gene products will be studied to define mechanisms of regulation. Searches will continue for new candidate genes critical to fertility, and the role of a sperm-specific sodium/hydrogen exchanger (sNHE) in capacitation and induction of the acrosome reaction will be delineated.
Specific Aim 2 is a detailed analysis of candidate gene product regulation. The sNHE will serve as the primary prototype for other candidate gene products. Studies will concentrate on mechanisms of regulation of the sNHE (e.g. the effects of covalent modification and associated proteins on sNHE activity). Based on these studies, linkage maps will begin to connect pathways from the sNHE, or other candidate gene products, to sperm behavioral responses such as motility activation or induction of the acrosome reaction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD036022-06
Application #
6873217
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Rankin, Tracy L
Project Start
2000-02-01
Project End
2010-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
6
Fiscal Year
2005
Total Cost
$315,900
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Abid, Shadaan N; Richardson, Timothy E; Powell, Heather M et al. (2014) A-single spermatogonia heterogeneity and cell cycles synchronize with rat seminiferous epithelium stages VIII-IX. Biol Reprod 90:32
Chapman, Karen M; Powell, Heather M; Chaudhary, Jaideep et al. (2013) Linking spermatid ribonucleic acid (RNA) binding protein and retrogene diversity to reproductive success. Mol Cell Proteomics 12:3221-36
Ivics, Zoltan; Izsvak, Zsuzsanna; Chapman, Karen M et al. (2011) Sleeping Beauty transposon mutagenesis of the rat genome in spermatogonial stem cells. Methods 53:356-65
Ivics, Zoltan; Izsvak, Zsuzsanna; Medrano, Gerardo et al. (2011) Sleeping Beauty transposon mutagenesis in rat spermatogonial stem cells. Nat Protoc 6:1521-35
Frost, Robert J A; Hamra, F Kent; Richardson, James A et al. (2010) MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs. Proc Natl Acad Sci U S A 107:11847-52
Izsvak, Zsuzsanna; Frohlich, Janine; Grabundzija, Ivana et al. (2010) Generating knockout rats by transposon mutagenesis in spermatogonial stem cells. Nat Methods 7:443-5
Hamra, F Kent (2010) Gene targeting: Enter the rat. Nature 467:161-3
Carlson, Anne E; Burnett, Lindsey A; del Camino, Donato et al. (2009) Pharmacological targeting of native CatSper channels reveals a required role in maintenance of sperm hyperactivation. PLoS One 4:e6844
Nicholas, Cory R; Xu, Eugene Y; Banani, Salman F et al. (2009) Characterization of a Dazl-GFP germ cell-specific reporter. Genesis 47:74-84
Wang, Dan; Hu, Jie; Bobulescu, I Alexandru et al. (2007) A sperm-specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC). Proc Natl Acad Sci U S A 104:9325-30

Showing the most recent 10 out of 19 publications