Leukemia Inhibitory Factor As a Mediator of Primate Ovulation &Oocyte Maturation

Summary

Principal Investigator: Jon D Hennebold
Abstract: DESCRIPTION (provided by applicant): The cellular and molecular processes occurring within the primate follicle resulting in the release of a mature ovum (ovulation) that fertilizes and undergoes subsequent embryonic development are incompletely defined. Systematic and detailed characterizations of such events are necessary for advancing infertility treatments and developing novel, non-hormonal forms of contraception. In this regard, studies conducted by the P.I. using a high-throughput genomic approach led to the identification of most, if not all, genes whose expression increases through the periovulatory interval following an ovulatory stimulus. Such mRNAs are likely involved in activities necessary for follicle rupture, which include the formation of a hyaluronan-rich extracellular matrix between cumulus cells and the loss of their cell-cell contacts (cumulus-oocyte expansion;C-OE), as well as the cytoplasmic and nuclear maturation of the oocyte required for subsequent fertilization and embryonic development. From the resultant database and additional preliminary studies, it was discovered that leukemia inhibitory factor (LIF) mRNA and protein increased in the rhesus macaque follicle from undetectable levels before administration of an ovulatory stimulus (human chorionic gonadotropin;hCG;0 h controls) to peak values prior to (12 h post-hCG) and following ovulation (36 h post-hCG). Furthermore, mRNAs encoding downstream signaling components responsible for LIF action (glycoprotein 130, or gp130;janus kinase 1, or JAK1;signal transducer and activator of transcription 3, or STAT3) were also highest in unruptured rhesus macaque follicles 12 h after hCG administration and those that had ovulated 36 h post-hCG. The mRNAs encoding both cell surface LIF binding proteins (LIF receptor, or LIFR;gp130) were further localized to isolated oocytes and granulosa cells. Lastly, in pilot studies, intrafollicula injection of a LIF antagonist (the extracellular LIF binding portion of the LIFR;referred to as soluble LIFR or sLIFR) prevents rupture of the rhesus macaque follicle following an ovulatory stimulus, whereas injection of vehicle alone results in ovulation. Collectively, these findings support the hypothesis that LIF synthesis and signaling in the primate ovary is a critical regulator of events necessary for ovulation and formation of the corpus luteum (assessed in Aim 1);as well as for C-OE, reinitiation of oocyte meiosis, fertilization, and early embryonic development (assessed in Aim 2). Novel techniques involving intrafollicular injection of a LIF antagonist (sLIFR) will be employed to assess the role LIF plays in follicle rupture as well the formation of the corpus luteum (i.e., the ability to synthesize progesterone and estradiol). Isolated rhesus macaque cumulus-oocyte complexes (COCs) from non-luteinized follicles (i.e., pre-hCG) will be directly exposed to LIF to determine a direct effect of this cytokine on promoting C-OE, reinitiation of meiosis, fertilization, and embryonic development.
Funding Period: 2012-09-28 - 2014-07-31
more information: NIH RePORT

Research Grants

  1. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
  2. Origins and Biological Consequences of Human Infertility
    Linda C Giudice; Fiscal Year: 2013
  3. Protease regulation of ovarian recrudescence
    KELLY ANSLEY YOUNG; Fiscal Year: 2013
  4. REGULATION OF OVARIAN FUNCTION BY GONADOTROPIN
    JAIRAM K M MENON; Fiscal Year: 2013
  5. Development of Superactive Analogs of FSH for Human Infertility
    BRUCE DALE WEINTRAUB; Fiscal Year: 2013
  6. Role of STARD6 in ovarian steroidogenesis
    HOLLY ANNE LAVOIE; Fiscal Year: 2013
  7. Oocyte-derived R-spondin2 as a Follicle Stimulating Hormone
    AARON JW HSUEH; Fiscal Year: 2013
  8. Rare Diseases Clinical Research Consortia (RDCRC) for the RDCR Network
    Mark L Batshaw; Fiscal Year: 2013
  9. Contraception by Blockade of Periovulatory Events in Primates
    Richard L Stouffer; Fiscal Year: 2013
  10. Male Contraception Research Center Grant
    William J Bremner; Fiscal Year: 2013

Detail Information

Research Grants30

  1. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
    ..This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease. ..
  2. Origins and Biological Consequences of Human Infertility
    Linda C Giudice; Fiscal Year: 2013
    ..abstract_text> ..
  3. Protease regulation of ovarian recrudescence
    KELLY ANSLEY YOUNG; Fiscal Year: 2013
    ..Our studies will provide potential non-hormonal targets for clinically- geared studies focused on "turning on" and "turning off" ovarian function. ..
  4. REGULATION OF OVARIAN FUNCTION BY GONADOTROPIN
    JAIRAM K M MENON; Fiscal Year: 2013
    ..The studies proposed here address novel questions that are central to reproductive endocrinology and the results might provide new insights into novel approaches for the treatment of infertility. ..
  5. Development of Superactive Analogs of FSH for Human Infertility
    BRUCE DALE WEINTRAUB; Fiscal Year: 2013
    ..We have licensed TR4401 to the worldwide leading veterinary superovulation company, Bioniche, Inc. for veterinary use, with a possible option to also co-develop the analog for human use. ..
  6. Role of STARD6 in ovarian steroidogenesis
    HOLLY ANNE LAVOIE; Fiscal Year: 2013
    ..Successful completion of this project will provide new insight into cholesterol trafficking for ovarian steroidogenesis and will serve as a basis for future studies of disorders of aberrant steroidogenesis by the ovary. ..
  7. Oocyte-derived R-spondin2 as a Follicle Stimulating Hormone
    AARON JW HSUEH; Fiscal Year: 2013
    ..This will be followed by the derivation of healthy pups as the basis for future clinical application using R-spondin2 to treat infertile patients with low FSH responses. ..
  8. Rare Diseases Clinical Research Consortia (RDCRC) for the RDCR Network
    Mark L Batshaw; Fiscal Year: 2013
    ..abstract_text> ..
  9. Contraception by Blockade of Periovulatory Events in Primates
    Richard L Stouffer; Fiscal Year: 2013
    ..abstract_text> ..
  10. Male Contraception Research Center Grant
    William J Bremner; Fiscal Year: 2013
    ..We hope that, in this way, our work will address critical needs of society. ..
  11. Cooperative Contraceptive Research Center: New Contraceptives with Dual Benefits
    REGINE SITRUK WARE; Fiscal Year: 2013
    ..SA2: Unravel molecular mechanism(s) by which adjudin-IMB disrupts adhesion protein complexes at the apical ectoplasmic specialization. SA3: Complete toxicity program to prepare for clinical use in men. ..
  12. Center for Reproductive Health After Disease
    Teresa K Woodruff; Fiscal Year: 2013
    ..abstract_text> ..
  13. LH ACTION IN OVARIAN CELL DIFFERENTIATION
    JoAnne S Richards; Fiscal Year: 2013
    ..Test the hypotheses that specific matrix factors, IL6 and innate immune cell-related genes expressed in cumulus cells direct the unique fate of these cells. ..
  14. 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. ..
  15. The role of chemokines in cumulus oocyte expansion (C-OE) and oocyte maturation
    MARINA CINTHIA PELUFFO; Fiscal Year: 2013
    ..abstract_text> ..
  16. 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. ..
  17. Functional Analysis of the Embryonic Epigenome in a Non-rodent Model
    Mark E Westhusin; Fiscal Year: 2013
    ....
  18. PROGESTERONE RECEPTOR AND ACTION IN THE PRIMATE OVARY
    Richard L Stouffer; Fiscal Year: 2013
    ....
  19. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  20. 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. ..
  21. Mitochondrial Gene Therapy
    Shoukhrat M Mitalipov; Fiscal Year: 2013
    ..In this study, we will explore feasibility, efficiency and safety of this novel mitochondrial gene replacement therapy in a clinically relevant nonhuman primate model. ..
  22. Hamster: a unique model for studying implantation
    BIBHASH CHANDRA PARIA; Fiscal Year: 2013
    ..abstract_text> ..
  23. 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. ..
  24. Harvard Reproductive Endocrine Sciences Center
    William Francis Crowley; Fiscal Year: 2013
    ..abstract_text> ..
  25. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  26. ANALYSIS OF REPRODUCTIVE FUNCTION USING TRANSGENIC MICE
    Martin M Matzuk; Fiscal Year: 2013
    ....