The cardiac myocyte has long been the primary focus of most studies attempting to elucidate the signaling mechanisms underlying heart failure. More recently the involvement of nonmyocytes has emerged as potentially just as important as myocytes in contributing to and controlling cardiac remodeling and progressive pathogenesis in heart failure. Specifically, the cardiac fibroblast and its ability to convert to myofibroblasts in promoting the fibrotic response and ventricular remodeling appears to be a highly underappreciated disease process with significant ramifications. Fibroblasts are activated in the heart in response to damage or due to neuroendocrine signaling, such as through Transforming Growth Factor Beta (TGFp). Here we hypothesize that the fibroblast responds to TGFp and other cytokines through select signaling pathways in promoting the fibrotic response and maladaptive remodeling in heart failure. We will examine both canonical (Smad2/3) and non-canonical (TAK1/p38a) TGFp signaling within fibroblasts to determine how these cells and their activation mediate disease in heart failure. All previous in vivo analyses of TGFp signaling and cardiac fibrosis have focused on the myocytes given available genetic tools. However, we have recently engineered a novel fibroblast-specific knock-in mouse iinodel to permit tamoxifen-regulated Cre activity in vivo. We will use this mouse to study fibroblast-based signaling during the development of cardiac disease.
Aim #1 will determine the necessary function of canonical TGFp signaling and Smad proteins in mediating cardiac fibrosis within the cardiac fibroblast itself.
Aim #2 will exaniine the role that non-canonical TGFp signaling plays through TAKI and p38a MAPK in mediating cardiac fibrosis, andj once again, our focus will be on signaling within the cardiac fibroblast only.
Aim #3 will examine a novel pathway that is calcium-TRPC6 activated and works in conjunction with TGFp signaling and other cytokines to pi^omote myofibroblast transdifferentiation in the heart and disease. These 3 specific aims will suggest for the first time the autonomous role for select signaling pathways from within the cardiac fibroblast in mediating myofibroblast transdifferentiation and fibrotic disease in the diseased heart. A number of potential therapeutic angles are suggested from the content of our project and emerging preliminary data.

Public Health Relevance

Our work focuses on the cardiac fibroblast, a cell in the heart that is known to be important in the scarring processes and remodeling that occur after cardiac injury. We intend to study how this cell functions during these disease processes and attempt to modulate its actions so that we can impact favorably on cardiac disease and heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL069779-12
Application #
8728999
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Travers, Joshua G; Kamal, Fadia A; Robbins, Jeffrey et al. (2016) Cardiac Fibrosis: The Fibroblast Awakens. Circ Res 118:1021-40
Schwanekamp, Jennifer A; Lorts, Angela; Vagnozzi, Ronald J et al. (2016) Deletion of Periostin Protects Against Atherosclerosis in Mice by Altering Inflammation and Extracellular Matrix Remodeling. Arterioscler Thromb Vasc Biol 36:60-8
Bernardo, Bianca C; Blaxall, Burns C (2016) From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure. Heart Lung Circ 25:425-34
Valiente-Alandi, Iñigo; Schafer, Allison E; Blaxall, Burns C (2016) Extracellular matrix-mediated cellular communication in the heart. J Mol Cell Cardiol 91:228-37
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Fang, Ming; Xiang, Fu-Li; Braitsch, Caitlin M et al. (2016) Epicardium-derived fibroblasts in heart development and disease. J Mol Cell Cardiol 91:23-7
James, Jeanne; Robbins, Jeffrey (2016) Healing a Heart Through Genetic Intervention. Circ Res 118:920-2
Travers, Joshua G; Schafer, Allison E; Blaxall, Burns C (2016) GRK2 in Lymphocytes: Expanding the Arsenal of Heart Failure Prognostics. Circ Res 118:1049-51
Previs, Michael J; Mun, Ji Young; Michalek, Arthur J et al. (2016) Phosphorylation and calcium antagonistically tune myosin-binding protein C's structure and function. Proc Natl Acad Sci U S A 113:3239-44
Gupta, Manish K; McLendon, Patrick M; Gulick, James et al. (2016) UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts. Circ Res 118:1894-905

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