The molecular mechanisms of prostaglandin action are of considerable importance to reproductive biologists, immunologists, neurobiologists, and oncologists. Aspirin and other non-steroidal anti- inflammatory drugs (NSAIDs) specifically inhibit prostaglandin synthesis and are associated with cancer prevention and reversible infertility. Prostaglandins are essential for ovulation and fertilization, but the molecular mechanisms are not well understood. The mouse is the only genetic system currently available to study prostaglandin functions during reproduction. The objective of this application is to determine the extent to which the nematode model Caenorhabditis elegans can be used to address fundamental questions in prostaglandin biology. To achieve this objective, we will test the central hypothesis that oocytes synthesize prostaglandins to regulate ovulation and sperm guidance. Support for this hypothesis comes from preliminary data showing that prostaglandin precursors, polyunsaturated fatty acids (PUFAs), and predicted prostaglandin synthases are required for these processes. In addition, prostaglandins can regulate sperm motility in the absence of PUFAs.
Our first aim i s to delineate a prostaglandin biosynthesis pathway that functions in oocytes. To achieve this aim, we will characterize predicted prostaglandin biosynthesis enzymes at the genetic and biochemical levels.
Our second aim i s to determine the extent to which prostaglandins and NSAIDs influence fertilization. To achieve this aim, we will examine the effects of prostaglandins and NSAIDs on sperm motility and ovulation in vivo.
Our final aim i s to identify the PUFA-derived signals synthesized by oocytes. A combination of genetics and liquid chromatography coupled to electrospray ionization tandem mass spectrometry will be used to achieve this aim. We expect that completing the proposed aims will establish the C. elegans gonad as the first simple, genetically tractable model for discovering molecular mechanisms of prostaglandin action during reproduction. These studies should lead to a comprehensive delineation of genes that are required for prostaglandin synthesis and function, any of which could encode new drug targets. The role of prostaglandins in fertilization could be conserved in mammals, an idea supported by prostaglandin deficient mice. Regardless, basic research on prostaglandins in the C. elegans gonad has the potential for discovering molecular mechanisms of human infertility, contraception, and cancer. Project Narrative Prostaglandins are lipid signals that are critical for human reproduction, immunity, and cardiovascular functions. Basic research on prostaglandins in the ovary has the potential for discovering molecular mechanisms of cancer, infertility, and contraception. The objective of this proposal is to determine the extent to which the model system Caenorhabditis elegans can be used to elucidate the molecular mechanisms of prostaglandin action during reproduction.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085105-05
Application #
8269764
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Okita, Richard T
Project Start
2008-07-01
Project End
2014-07-31
Budget Start
2012-05-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$238,753
Indirect Cost
$74,096
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Hoang, Hieu D; Prasain, Jeevan K; Dorand, Dixon et al. (2013) A heterogeneous mixture of F-series prostaglandins promotes sperm guidance in the Caenorhabditis elegans reproductive tract. PLoS Genet 9:e1003271
Prasain, Jeevan K; Hoang, Hieu D; Edmonds, Johnathan W et al. (2013) Prostaglandin extraction and analysis in Caenorhabditis elegans. J Vis Exp :
Edmonds, Johnathan W; McKinney, Shauna L; Prasain, Jeevan K et al. (2011) The gap junctional protein INX-14 functions in oocyte precursors to promote C. elegans sperm guidance. Dev Biol 359:47-58
Edmonds, Johnathan W; Prasain, Jeevan K; Dorand, Dixon et al. (2010) Insulin/FOXO signaling regulates ovarian prostaglandins critical for reproduction. Dev Cell 19:858-71
Han, Sung Min; Cottee, Pauline A; Miller, Michael A (2010) Sperm and oocyte communication mechanisms controlling C. elegans fertility. Dev Dyn 239:1265-81