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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Okita, Richard T
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University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
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Hoang, Hieu D; Miller, Michael A (2017) Sperm Navigation Mechanisms in the Female Reproductive Tract. Results Probl Cell Differ 59:241-267
Cottee, Pauline A; Cole, Tim; Schultz, Jessica et al. (2017) The C. elegans VAPB homolog VPR-1 is a permissive signal for gonad development. Development 144:2187-2199
Hoang, Hieu D; Miller, Michael A (2017) Chemosensory and hyperoxia circuits in C. elegans males influence sperm navigational capacity. PLoS Biol 15:e2002047
Pier, Bruce; Edmonds, Johnathan W; Wilson, Landon et al. (2017) Comprehensive profiling of prostaglandins in human ovarian follicular fluid using mass spectrometry. Prostaglandins Other Lipid Mediat 134:7-15
Miller, Michael A (2015) Patterning with Diffusion Barriers. Dev Cell 35:395-6
Prasain, Jeevan K; Wilson, Landon; Hoang, Hieu D et al. (2015) Comparative Lipidomics of Caenorhabditis elegans Metabolic Disease Models by SWATH Non-Targeted Tandem Mass Spectrometry. Metabolites 5:677-96
McKnight, Katherine; Hoang, Hieu D; Prasain, Jeevan K et al. (2014) Neurosensory perception of environmental cues modulates sperm motility critical for fertilization. Science 344:754-7
Prasain, Jeevan K; Hoang, Hieu D; Edmonds, Johnathan W et al. (2013) Prostaglandin extraction and analysis in Caenorhabditis elegans. J Vis Exp :
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
Miller, Michael A; Chin-Sang, Ian D (2012) Eph receptor signaling in C. elegans. WormBook :1-17

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