Prostaglandins in C. elegans Fertilization
Principal Investigator: Michael A Miller
Abstract: Project Summary 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 is 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 is 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 is 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.
Funding Period: 2008-07-01 - 2014-07-31
more information: NIH RePORT
- Sperm and oocyte communication mechanisms controlling C. elegans fertilitySung Min Han
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
Dev Dyn 239:1265-81. 2010..Here we review sperm and oocyte communication in C. elegans and discuss relationships to human disorders...
- Insulin/FOXO signaling regulates ovarian prostaglandins critical for reproductionJohnathan W Edmonds
Department of Cell Biology, University of Alabama at Birmingham, 35294, USA
Dev Cell 19:858-71. 2010..Prostaglandins may be conserved sperm guidance factors and widespread downstream effectors of insulin actions that influence both reproductive and nonreproductive processes...
- The gap junctional protein INX-14 functions in oocyte precursors to promote C. elegans sperm guidanceJohnathan W Edmonds
Department of Cell Biology, University of Alabama at Birmingham, AL 35294, USA
Dev Biol 359:47-58. 2011..We propose that this mechanism regulates the transcription of a factor(s) that modulates prostaglandin metabolism, transport, or activity in the reproductive tract...
- A heterogeneous mixture of F-series prostaglandins promotes sperm guidance in the Caenorhabditis elegans reproductive tractHieu D Hoang
Department of Cell Biology, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
PLoS Genet 9:e1003271. 2013..This cyclooxygenase-independent pathway for F-series synthesis may be conserved...
- Neurosensory perception of environmental cues modulates sperm motility critical for fertilizationKatherine McKnight
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Science 344:754-7. 2014..Our data indicate that environmental cues perceived by the female nervous system affect sperm function. ..
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