This application arises from observations made in the last six years while examining the cellular and molecular role of inflammation in the regulation of cardiac repair. The studies were directed at understanding the potential role of 1) chemokine regulation and 2) marrow-derived blood-borne precursors in cardiac injury and repair. As part of these studies, we defined a model of fibrotic cardiomyopathy in the mouse arising from daily, non-lethal coronary occlusion and reperfusion (I/RC). Both the fibrosis and the myocardial dysfunction are obviated by 1) overexpression of extracellular SOD and 2) deletion or antibody inhibition of MCP-1. Our data suggest that the non-adaptive fibrosis is associated with the uptake of marrow-derived blood-borne fibroblast precursors. Non-adaptive fibrosis and remodeling in coronary artery disease is clearly one of the leading causes of heart failure and death even in the absence of infarction. The primary model to be studied in this grant period involves this fibrotic cardiomyopathy (I/RC) in the mouse developing in the absence of myocardial infarction. This model offers the opportunity to concentrate on the role of dysregulation of chemokine expression and the uptake and maturation of the marrow-derived blood- borne fibroblast precursors which generate the activated fibroblasts associated with non-adaptive cardiac fibrosis.
Specific Aim 1 - Characterize and quantitate factors mediating the uptake and maturation of blood-derived fibroblast precursors which mediate non-adaptive fibrosis in I/RC.
Specific Aim 2 - Examine the cellular and molecular mechanisms of interventions which we have shown to obviate I/RC by specifically altering the growth of blood-derived precursors and/or their maturation into secretory fibroblasts in vivo and in vitro. We will examine the cellular and molecular consequences of: a) treatment with serum amyloid P and b) Rho kinase (ROCK1) deletion. We will also examine the effect of IP10, a CXC chemokine that inhibits fibrosis by modulating fibroblast function and impairs myocardial scar formation following infarction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089792-02
Application #
7501356
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
2007-09-30
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$382,500
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Yuguo; Jia, Li; Hu, Zhaoyong et al. (2018) AMP-activated protein kinase/myocardin-related transcription factor-A signaling regulates fibroblast activation and renal fibrosis. Kidney Int 93:81-94
Suh, Ji Ho; Lai, Li; Nam, Deokhwa et al. (2017) Steroid receptor coactivator-2 (SRC-2) coordinates cardiomyocyte paracrine signaling to promote pressure overload-induced angiogenesis. J Biol Chem 292:21643-21652
Cieslik, Katarzyna A; Trial, JoAnn; Entman, Mark L (2017) Aicar treatment reduces interstitial fibrosis in aging mice: Suppression of the inflammatory fibroblast. J Mol Cell Cardiol 111:81-85
Trial, JoAnn; Heredia, Celia Pena; Taffet, George E et al. (2017) Dissecting the role of myeloid and mesenchymal fibroblasts in age-dependent cardiac fibrosis. Basic Res Cardiol 112:34
Mayr, Magdalena; Duerrschmid, Clemens; Medrano, Guillermo et al. (2016) TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function. Physiol Rep 4:
Crawford, Jeffrey R; Trial, JoAnn; Nambi, Vijay et al. (2016) Plasma Levels of Endothelial Microparticles Bearing Monomeric C-reactive Protein are Increased in Peripheral Artery Disease. J Cardiovasc Transl Res 9:184-93
Trial, JoAnn; Cieslik, Katarzyna A; Entman, Mark L (2016) Phosphocholine-containing ligands direct CRP induction of M2 macrophage polarization independent of T cell polarization: Implication for chronic inflammatory states. Immun Inflamm Dis 4:274-88
Trial, JoAnn; Entman, Mark L; Cieslik, Katarzyna A (2016) Mesenchymal stem cell-derived inflammatory fibroblasts mediate interstitial fibrosis in the aging heart. J Mol Cell Cardiol 91:28-34
Trial, JoAnn; Potempa, Lawrence A; Entman, Mark L (2016) The role of C-reactive protein in innate and acquired inflammation: new perspectives. Inflamm Cell Signal 3:
Medrano, Guillermo; Hermosillo-Rodriguez, Jesus; Pham, Thuy et al. (2016) Left Atrial Volume and Pulmonary Artery Diameter Are Noninvasive Measures of Age-Related Diastolic Dysfunction in Mice. J Gerontol A Biol Sci Med Sci 71:1141-50

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