Prostaglandins in C. elegans Fertilization

Summary

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

Top Publications

  1. pmc Sperm and oocyte communication mechanisms controlling C. elegans fertility
    Sung Min Han
    Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    Dev Dyn 239:1265-81. 2010
  2. pmc Insulin/FOXO signaling regulates ovarian prostaglandins critical for reproduction
    Johnathan W Edmonds
    Department of Cell Biology, University of Alabama at Birmingham, 35294, USA
    Dev Cell 19:858-71. 2010
  3. pmc The gap junctional protein INX-14 functions in oocyte precursors to promote C. elegans sperm guidance
    Johnathan W Edmonds
    Department of Cell Biology, University of Alabama at Birmingham, AL 35294, USA
    Dev Biol 359:47-58. 2011
  4. pmc A heterogeneous mixture of F-series prostaglandins promotes sperm guidance in the Caenorhabditis elegans reproductive tract
    Hieu 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
  5. pmc Neurosensory perception of environmental cues modulates sperm motility critical for fertilization
    Katherine 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

Research Grants

Detail Information

Publications7

  1. pmc Sperm and oocyte communication mechanisms controlling C. elegans fertility
    Sung 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...
  2. pmc Insulin/FOXO signaling regulates ovarian prostaglandins critical for reproduction
    Johnathan 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...
  3. pmc The gap junctional protein INX-14 functions in oocyte precursors to promote C. elegans sperm guidance
    Johnathan 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...
  4. pmc A heterogeneous mixture of F-series prostaglandins promotes sperm guidance in the Caenorhabditis elegans reproductive tract
    Hieu 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...
  5. pmc Neurosensory perception of environmental cues modulates sperm motility critical for fertilization
    Katherine 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. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  3. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  4. Lineage tracing of germline stem cell differentiation in adult ovaries
    Ning Wang; Fiscal Year: 2013
    ....
  5. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  6. Contraception by Blockade of Periovulatory Events in Primates
    Richard L Stouffer; Fiscal Year: 2013
    ..abstract_text> ..
  7. Secreted RNA during CRC progression biogenesis function and clinical markers
    Robert J Coffey; Fiscal Year: 2013
    ..We are confident that these specific RNA trafficking mechanisms will be acting in other tissues in the body and are of general relevance to multiple fields. ..
  8. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  9. Clinical Translational Research Center for Neurodevelopmental Disorders
    Joseph Piven; Fiscal Year: 2013
    ..abstract_text> ..
  10. CANCER CENTER SUPPORT GRANT
    Nancy E Davidson; Fiscal Year: 2013
    ..abstract_text> ..
  11. CANCER CENTER SUPPORT GRANT
    Mark A Israel; Fiscal Year: 2013
    ..abstract_text> ..
  12. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..
  13. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  14. Cellular/Molecular Pathophysiology of Intellectual and Developmental Disabilities
    Stuart A Lipton; Fiscal Year: 2013
    ..The CORE supports administration, statistics, tissue culture, and crystallography/modeling of NMDAR subunits and functional sites, all critical to the proposed Projects. ..
  15. Origins and Biological Consequences of Human Infertility
    Linda C Giudice; Fiscal Year: 2013
    ..abstract_text> ..
  16. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  17. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  18. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  19. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  20. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  21. Human Exposure to Bisphenol A, Phthalates and Fertility, Pregnancy Outcomes
    Russ B Hauser; Fiscal Year: 2013
    ..abstract_text> ..