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)
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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Sandri, Marco; Robbins, Jeffrey (2014) Proteotoxicity: an underappreciated pathology in cardiac disease. J Mol Cell Cardiol 71:3-10
Molkentin, Jeffery D (2014) Letter by Molkentin regarding article, "The absence of evidence is not evidence of absence: the pitfalls of Cre Knock-Ins in the c-Kit Locus". Circ Res 115:e21-3
Gupta, Manish K; Robbins, Jeffrey (2014) Post-translational control of cardiac hemodynamics through myosin binding protein C. Pflugers Arch 466:231-6
Mun, Ji Young; Previs, Michael J; Yu, Hope Y et al. (2014) Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. Proc Natl Acad Sci U S A 111:2170-5
Wang, Xuejun; Robbins, Jeffrey (2014) Proteasomal and lysosomal protein degradation and heart disease. J Mol Cell Cardiol 71:16-24
Gupta, Manish K; Gulick, James; Liu, Ruijie et al. (2014) Sumo E2 enzyme UBC9 is required for efficient protein quality control in cardiomyocytes. Circ Res 115:721-9
Sengupta, Arunima; Kalinichenko, Vladimir V; Yutzey, Katherine E (2013) FoxO1 and FoxM1 transcription factors have antagonistic functions in neonatal cardiomyocyte cell-cycle withdrawal and IGF1 gene regulation. Circ Res 112:267-77
Chakraborty, Santanu; Sengupta, Arunima; Yutzey, Katherine E (2013) Tbx20 promotes cardiomyocyte proliferation and persistence of fetal characteristics in adult mouse hearts. J Mol Cell Cardiol 62:203-13
Braitsch, Caitlin M; Kanisicak, Onur; van Berlo, Jop H et al. (2013) Differential expression of embryonic epicardial progenitor markers and localization of cardiac fibrosis in adult ischemic injury and hypertensive heart disease. J Mol Cell Cardiol 65:108-19
Razzaque, Md Abdur; Gupta, Manish; Osinska, Hanna et al. (2013) An endogenously produced fragment of cardiac myosin-binding protein C is pathogenic and can lead to heart failure. Circ Res 113:553-61

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