Role of 12/15-lipoxygenase pathway in implantation

Summary

Principal Investigator: MILAN BAGCHI
Affiliation: University of Illinois
Country: USA
Abstract: The objective of this proposal is to investigate the functional role of the lipid mediators generated by the 12/15-lipoxygenase (12/15-LOX) enzymes in the control of uterine function during implantation. The 12/15-LOX catalyzes the stereo-specific oxygenation of the 20-carbon polyunsaturated fatty acids, arachidonic acid and linoleic acid, into a complex series of derivatives, HETEs and HODES. Recent studies, using high-density oligonucleotide microarrays, revealed that progesterone markedly induces the synthesis of mRNAs encoding the 12/15-LOX family members, leukocyte-12/15-LOX and epidermal-12/15-LOX, in the surface epithelium of pregnant uterus precisely at the time of implantation. Administration of a LOX-specific inhibitor markedly inhibited steroid hormone-regulated vascular permeability during delayed implantation in mice, indicating an important role of these enzymes in creating a receptive uterus. The major goals of this proposal are to: 1. Identify the gene networks that mediate the physiological effects of these lipid metabolites in the uterus during implantation. The 12/15-LOX-regulated gene pathways will be identified by DNA microarray. The spatio-temporal expression of these genes in the peri-implantation uterus will be analyzed and their function will be determined by a newly developed antisense oligonucleotide strategy. 2. Investigate the role of PPARgamma in the 12/15-LOX signaling pathway during implantation. The 12/15-LOX-derived metabolites of arachidonic or linoleic acid activate gene transcription by the peroxisome proliferator-activated receptor gamma (PPARgamma) in cell-based assays. PPARgamma expression is also induced in the uterus in the peri-implantation period. We will test whether PPARgamma is indeed the endogenous receptor for the 12/15-LOX-derived metabolites in the peri-implantation uterus and identify its target genes in this tissue. The role of PPARgamma will be further investigated by generating a conditional knockout of its gene in the uterus and by analyzing the functional consequences of the loss-of-function mutation of this receptor during implantation. Collectively, the proposed experiments will test the hypothesis that a novel signaling pathway, involving 12/15-LOX-derived lipid mediators, PPARgamma, and its downstream target genes, regulates critical events during implantation.
Funding Period: 2003-07-01 - 2008-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Use of the progesterone receptor antagonist RU 486 to identify novel progesterone receptor-regulated pathways in implantation
    Indrani C Bagchi
    Department of Veterinary Biosciences and Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61802, USA
    Semin Reprod Med 23:38-45. 2005
  2. ncbi Identification of a signaling pathway involving progesterone receptor, calcitonin, and tissue tranglutaminase in Ishikawa endometrial cells
    Quanxi Li
    Department of Veterinary Biosciences, University of Illinois, Urbana, 61802, USA
    Endocrinology 147:2147-54. 2006
  3. ncbi C/EBPbeta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma
    Srinivasa Raju Mantena
    Department of Veterinary Biosciences, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 103:1870-5. 2006
  4. ncbi Control of uterine cell proliferation and differentiation by C/EBPbeta: functional implications for establishment of early pregnancy
    Milan K Bagchi
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    Cell Cycle 5:922-5. 2006
  5. ncbi A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice
    Gopinath S Palanisamy
    Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, USA
    Mol Endocrinol 20:2784-95. 2006
  6. ncbi Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human
    Quanxi Li
    Department of Veterinary Biosciences, University of Illinois at Urbana Champaign, Urbana, Illinois 61802, USA
    J Biol Chem 282:31725-32. 2007
  7. ncbi Peroxisome proliferator-activated receptor gamma is a target of progesterone regulation in the preovulatory follicles and controls ovulation in mice
    Jaeyeon Kim
    University of Illinois, MC 114, 534 Burrill Hall, 407 S Goodwin, Urbana, IL 61801, USA
    Mol Cell Biol 28:1770-82. 2008
  8. ncbi Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival
    Mary J Laws
    Department of Veterinary Biosciences, and University of Illinois Urbana Champaign, Urbana, IL 61802, USA
    Development 135:2659-68. 2008
  9. ncbi Signaling by hypoxia-inducible factors is critical for ovulation in mice
    Jaeyeon Kim
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    Endocrinology 150:3392-400. 2009

Scientific Experts

  • INDRANI BAGCHI
  • Milan K Bagchi
  • Quanxi Li
  • Jaeyeon Kim
  • Athilakshmi Kannan
  • Francesco J DeMayo
  • Mary J Laws
  • John P Lydon
  • Robert N Taylor
  • Marcey Sato
  • Srinivasa R Mantena
  • Srinivasa Raju Mantena
  • Gopinath S Palanisamy
  • Yong-Pil Cheon
  • David E Gutstein
  • Neil Sidell
  • Wei Wang
  • Peter F Johnson
  • Yong Pil Cheon
  • Regine L Sitruk-Ware

Detail Information

Publications9

  1. ncbi Use of the progesterone receptor antagonist RU 486 to identify novel progesterone receptor-regulated pathways in implantation
    Indrani C Bagchi
    Department of Veterinary Biosciences and Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61802, USA
    Semin Reprod Med 23:38-45. 2005
    ..This article provides a brief description of the expression and function of these newly identified molecular pathways...
  2. ncbi Identification of a signaling pathway involving progesterone receptor, calcitonin, and tissue tranglutaminase in Ishikawa endometrial cells
    Quanxi Li
    Department of Veterinary Biosciences, University of Illinois, Urbana, 61802, USA
    Endocrinology 147:2147-54. 2006
    ..In summary, we have uncovered a novel steroid-regulated signaling cascade in which P induces CT, which, in turn, induces tTGase and potentially plays a critical role in the human endometrium during implantation...
  3. ncbi C/EBPbeta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma
    Srinivasa Raju Mantena
    Department of Veterinary Biosciences, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 103:1870-5. 2006
    ..Collectively, our studies established that C/EBPbeta is a key mediator of steroid responsiveness of the epithelium and stroma in the mouse uterus...
  4. ncbi Control of uterine cell proliferation and differentiation by C/EBPbeta: functional implications for establishment of early pregnancy
    Milan K Bagchi
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    Cell Cycle 5:922-5. 2006
    ..It is postulated that C/EBPbeta controls the expression of critical molecules that regulate proliferation and function of epithelial and stromal cells in the female reproductive tract during the establishment of early pregnancy...
  5. ncbi A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice
    Gopinath S Palanisamy
    Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, USA
    Mol Endocrinol 20:2784-95. 2006
    ....
  6. ncbi Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human
    Quanxi Li
    Department of Veterinary Biosciences, University of Illinois at Urbana Champaign, Urbana, Illinois 61802, USA
    J Biol Chem 282:31725-32. 2007
    ..Collectively, our studies uncovered a unique conserved pathway involving BMP2 and Wnt4 that mediates P-induced stromal decidualization in the mouse and the human...
  7. ncbi Peroxisome proliferator-activated receptor gamma is a target of progesterone regulation in the preovulatory follicles and controls ovulation in mice
    Jaeyeon Kim
    University of Illinois, MC 114, 534 Burrill Hall, 407 S Goodwin, Urbana, IL 61801, USA
    Mol Cell Biol 28:1770-82. 2008
    ..Collectively, these studies revealed that PPARgamma is a key mediator of the biological actions of PR in the granulosa cells and activation of its downstream pathways critically controls ovulation...
  8. ncbi Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival
    Mary J Laws
    Department of Veterinary Biosciences, and University of Illinois Urbana Champaign, Urbana, IL 61802, USA
    Development 135:2659-68. 2008
    ....
  9. ncbi Signaling by hypoxia-inducible factors is critical for ovulation in mice
    Jaeyeon Kim
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    Endocrinology 150:3392-400. 2009
    ..Collectively, these findings unveiled a novel ovarian role for the HIF transcription factors during the ovulatory period in mice...