The central objective of our Program Project Grant """"""""Signaling Processes Underlying Cardiovascular Function,"""""""" is to extend our investigation of integrating specific signaling pathways underlying cardiac function to normal and pathogenic fibrosis. The central hypothesis is that the signaling pathways centered in the fibroblast are critical to the fibrotic processes characteristic of so much cardiovascular disease and heart failure. There is truly a remarkable lack of data and understanding as to if and how fibroblasts themselves contribute to cardiac disease. The 3 Projects will direct their efforts at determining the exact identity of the signaling pathways within fibroblasts that mediate myofibroblast transformation and longstanding fibrosis in surgically, pharmacologically- and genetically-induced cardiac disease. All of the Projects will also attempt to identify therapeutic windows for impacting favorably on the processes'pathogenic consequences. Our group consists of 3 Project Leaders and 4 Core-oriented investigators who have a track record of sustained and productive collaboration. The synergy and collaborations that underlie the PPG are underscored by the commonality of approach and the seamless use of models across the Projects. The goal of this Program is to prove proof-of-concept of fibroblast-based signaling pathways'importance in cardiac disease. Project 1's title is: Fibrotic signaling in cardiomyopathy. Jeffrey Robbins, Ph.D., Professor of Pediatrics, will focus on testing the central hypothesis that TGF? signaling processes that are fibroblast-based play a critical role in the fibrotic response in sarcomere-based and nonsarcomere- based disease. Project 2's title is: Wnt/?-catenin signaling and cardiac fibrosis. Katherine Yutzey, Ph.D., Professor of Pediatrics, will test the hypothesis that Wnt/?-catenin signaling promotes normal development of interstitial fibroblasts and also contributes to pathologic interstitial fibrosis in adult cardiovascular disease. Project 3's title s: TGF? signaling and its role in cardiac fibrosis. Jeffery Molkentin, PhD., Professor of Pediatrics, will focus on canonical and non-canonical TGF? signaling in the cardiac fibroblast during cardiac disease development induced as a result of surgical intervention. The hypothesis is that the fibroblast responds to TGF? and other cytokines through select signaling pathways in promoting fibrosis and maladaptive remodeling. These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core.

Public Health Relevance

The cardiac fibroblast is a major cell type in the heart. Recent data now show that the fibroblast is also heavily involved in the pathogenic processes that accompany cardiac disease. Using novel and newly developed tools, we will manipulate the fibroblast's proteins during cardiac disease and see if we can modify development of cardiac fibrosis and chamber remodeling. Our ability to impact favorably on these processes would open up many novel therapeutic avenues for impacting on cardiovascular disease and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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Adhikari, Bishow B
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Singh, Sonia R; Robbins, Jeffrey (2018) Desmin and Cardiac Disease: An Unfolding Story. Circ Res 122:1324-1326
Lowey, Susan; Bretton, Vera; Joel, Peteranne B et al. (2018) Hypertrophic cardiomyopathy R403Q mutation in rabbit ?-myosin reduces contractile function at the molecular and myofibrillar levels. Proc Natl Acad Sci U S A 115:11238-11243
Valiente-Alandi, IƱigo; Potter, Sarah J; Salvador, Ane M et al. (2018) Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure. Circulation 138:1236-1252
Meng, Qinghang; Bhandary, Bidur; Bhuiyan, Md Shenuarin et al. (2018) Myofibroblast-Specific TGF? Receptor II Signaling in the Fibrotic Response to Cardiac Myosin Binding Protein C-Induced Cardiomyopathy. Circ Res 123:1285-1297
Singh, Sonia R; Zech, Antonia T L; Geertz, Birgit et al. (2017) Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice. Circ Heart Fail 10:
Xiang, Fu-Li; Fang, Ming; Yutzey, Katherine E (2017) Loss of ?-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice. Nat Commun 8:712
Kamal, Fadia A; Travers, Joshua G; Schafer, Allison E et al. (2017) G Protein-Coupled Receptor-G-Protein ??-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure. J Am Soc Nephrol 28:197-208
Khalil, Hadi; Kanisicak, Onur; Prasad, Vikram et al. (2017) Fibroblast-specific TGF-?-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest 127:3770-3783
McLendon, Patrick M; Davis, Gregory; Gulick, James et al. (2017) An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels. Circ Res 121:604-616
Rudomanova, Valeria; Blaxall, Burns C (2017) Targeting GPCR-G??-GRK2 signaling as a novel strategy for treating cardiorenal pathologies. Biochim Biophys Acta Mol Basis Dis 1863:1883-1892

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