Mechanisms of cardiac fibrosis

Summary

Principal Investigator: April Stempien Otero
Abstract: The primary goal of this proposal is to train the principal investigator to become an independent laboratory based investigator in the field of cardiac failure. To accomplish this goal, the principal investigator proposes a detailed training program in the investigation of the mechanisms of cardiac fibrosis in a transgenic mouse model. Several key collaborators will assist in this goal. They include her sponsor, Dr. David Dichek, an expert in gene manipulation in animal models of cardiovascular disease. Dr. Charles Murry, Pathology, will assist in the analysis of myocardial histology. In addition, the principal investigator presents a training plan including specific coursework, conferences, and the formation of an advisory committee to guide her development as a physician-scientist. Cardiac fibrosis is a common finding in end-stage heart failure independent of etiology. Mechanisms leading to the development of cardiac fibrosis are poorly defined. Recent work in the Dichek lab has indicated a possible role for urokinase plasminogen activator(uPA) in cardiac fibrosis. To define mechanisms involved in the development of cardiac fibrosis, the candidate proposes the following specific aims. 1)To test the hypothesis that cardiac fibrosis is mediated by increased activation of latent transforming growth factor-beta 1 (TGF-beta1) leading to increased fibroblast activation. 2) To determine the role of plasminogen, matrix metalloproteinases and the uPA receptor in cardiac fibrosis. 3) To test the hypothesis that altered gene expression by bone marrow derived cells is sufficient to modulate cardiac fibrosis. The University of Washington has outstanding resources for the development of physician-scientists in cardiovascular diseases. There exists a strong collaborative approach to the study of cardiovascular biology between various departments and core laboratories. This environment will allow the principal investigator to gain both the technical expertise and the critical thinking skills necessary to develop into an independent investigator in cardiac failure.
Funding Period: 2002-07-22 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. pmc Urokinase plasminogen activator induces pro-fibrotic/m2 phenotype in murine cardiac macrophages
    Jessica Meznarich
    University of Washington School of Medicine, Division of Cardiology, Seattle, Washington, United States of America
    PLoS ONE 8:e57837. 2013
  2. pmc The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling
    Elina Minami
    University of Washington School of Medicine, Division of Cardiology, Seattle, WA 98195, USA
    J Mol Cell Cardiol 49:516-24. 2010
  3. pmc Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice
    Michal Kremen
    Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA
    Proc Natl Acad Sci U S A 105:17109-14. 2008
  4. pmc TGF-[beta]1 limits plaque growth, stabilizes plaque structure, and prevents aortic dilation in apolipoprotein E-null mice
    Andrew D Frutkin
    Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195 7710, USA
    Arterioscler Thromb Vasc Biol 29:1251-7. 2009

Detail Information

Publications4

  1. pmc Urokinase plasminogen activator induces pro-fibrotic/m2 phenotype in murine cardiac macrophages
    Jessica Meznarich
    University of Washington School of Medicine, Division of Cardiology, Seattle, Washington, United States of America
    PLoS ONE 8:e57837. 2013
    ..Therefore, we sought to determine if uPA induces changes in macrophage function that promote cardiac collagen accumulation...
  2. pmc The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling
    Elina Minami
    University of Washington School of Medicine, Division of Cardiology, Seattle, WA 98195, USA
    J Mol Cell Cardiol 49:516-24. 2010
    ..We hypothesize that plasmin generation in the heart in response to injury may induce activation of macrophages to a profibrotic phenotype to allow rapid formation of collagenous scar...
  3. pmc Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice
    Michal Kremen
    Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA
    Proc Natl Acad Sci U S A 105:17109-14. 2008
    ....
  4. pmc TGF-[beta]1 limits plaque growth, stabilizes plaque structure, and prevents aortic dilation in apolipoprotein E-null mice
    Andrew D Frutkin
    Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195 7710, USA
    Arterioscler Thromb Vasc Biol 29:1251-7. 2009
    ..The role of TGF-beta1 in aneurysm formation is also controversial. We tested whether overexpression of active TGF-beta1 in hyperlipidemic mice affects atherogenesis and aortic dilation...