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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL069779-11
Application #
8413660
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wong, Renee P
Project Start
2002-06-06
Project End
2018-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$1,706,890
Indirect Cost
$556,978
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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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
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Xiang, Fu-Li; Guo, Minzhe; Yutzey, Katherine E (2016) Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction. Circulation 133:1081-92
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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