Corneal Repair: uPA and extracellular matrix

Summary

Principal Investigator: Audrey Bernstein
Abstract: DESCRIPTION: Corneal wound healing without scarring regenerates corneal transparency. Corneas that heal with scarring have opacities and obstructed vision. Thus, understanding the pathways that influence regenerative rather than fibrotic healing is an essential step towards therapeutically promoting healthy repair. Upon corneal wounding, the normally quiescent cells in the stroma differentiate into fibroblasts, which secrete proteases as they migrate. This proposal is focused on the contributions of the extracellular serine protease, urokinase-type plasminogen activator (uPA), which is expressed by corneal fibroblasts after wounding. When uPA binds to its cell-surface receptor, uPAR, uPA generates plasmin at the cell-matrix interface. Plasmin degrades extracellular matrix (ECM) and activates latent growth factors such as TGF. TGF stimulates fibroblast proliferation and migration, and induces the differentiation of motile fibroblasts into non-motile myofibroblasts, which are essential for matrix contraction and wound closure. One way in which TGF may be eliciting its dual effects is through the induction of plasminogen activation inhibitor (PAI-1) expression. There is a significant body of data that the opposing effects of PAI-1 are concentration dependent: low concentrations of PAI-1 induce cell proliferation and migration, whereas, high concentrations inhibit these processes. The hypothesis being tested in this proposal is that after corneal wounding, local PAI-1 concentrations are mediated by binding to Vn. Further, that low concentrations of PAI-1 result in corneal fibroblast proliferation and migration whereas high concentrations of PAI-1 induce uPA/uPAR downregulation and result in myofibroblast differentiation. The specific aims are to determine if 1) TGF concentration regulates PAI-1 levels, uPA activity, and myofibroblast differentiation. 2) Vn mediates the effects of TGF and PAI-1 on uPA activity, cell migration, and myofibroblast differentiation. 3) Vn, PAI-1 and integrin expression change throughout wound healing with changing stromal phenotypes. 4) uPAR cleavage into a non-uPA binding form inhibits cell migration and induces myofibroblast differentiation. The results of these studies will lead to a better understanding of the mechanisms that guide regenerative wound repair.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc uPA binding to PAI-1 induces corneal myofibroblast differentiation on vitronectin
    Lingyan Wang
    Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York 10029, USA
    Invest Ophthalmol Vis Sci 53:4765-75. 2012
  2. pmc Concentration-dependent effects of transforming growth factor β1 on corneal wound healing
    Lingyan Wang
    Mount Sinai School of Medicine, Dept of Ophthalmology, New York, NY 10029, USA
    Mol Vis 17:2835-46. 2011
  3. pmc Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly
    Lingyan Wang
    Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York, United States of America
    PLoS ONE 7:e33915. 2012

Scientific Experts

  • Audrey Bernstein
  • Lingyan Wang
  • Erin E Meyers
  • Benjamin S Pedroja
  • Chun Ying Ko
  • Sally S Twining
  • Angelo L Garcia
  • Daniel A Lawrence
  • Christine M Ly
  • Nadia Pelaez

Detail Information

Publications3

  1. pmc uPA binding to PAI-1 induces corneal myofibroblast differentiation on vitronectin
    Lingyan Wang
    Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York 10029, USA
    Invest Ophthalmol Vis Sci 53:4765-75. 2012
    ..Because fibrotic Mfs secrete elevated amounts of urokinase plasminogen activator (uPA), we tested whether increased extracellular uPA promotes the persistence of Mfs on VN...
  2. pmc Concentration-dependent effects of transforming growth factor β1 on corneal wound healing
    Lingyan Wang
    Mount Sinai School of Medicine, Dept of Ophthalmology, New York, NY 10029, USA
    Mol Vis 17:2835-46. 2011
    ..Although high concentrations of TGFβ1 leads to scarring, we asked whether low concentrations of TGFβ1 could promote wound healing without generating a large fibrotic response...
  3. pmc Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly
    Lingyan Wang
    Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York, United States of America
    PLoS ONE 7:e33915. 2012
    ..Our data support a novel mechanism by which downregulation of uPA/uPAR results in increased integrin αvβ5 cell-surface protein levels that regulate the activity of β1 integrins, promoting characteristics of the persistent Mf...