Cardiovascular disease is one of the leading causes of death in the US, and the inability to repair damaged muscle is a major obstacle in treating heart disease. Currently, there are no definitive methods to improve heart function after a heart attack, and a common result is permanent muscle loss. While a significant amount of research has focused on the ability to expand or generate cardiomyocytes for replacement of the damaged tissue, less focus has been placed on controlling the detrimental effects of fibrosis and enhancing the beneficial effects of angiogenesis. Additional information on the epicardium, or outer layer of the heart, may provide insights into these processes. Studies have demonstrated that epicardial cells differentiate into cardiomyocytes, vascular smooth muscle cells, endothelial cells, and fibroblasts, and an in depth knowledge of the mechanisms that cause these cell populations to form in the embryonic heart will be essential for programming the adult epicardium to generate these cell types after heart injury. Platelet derived growth factor (PDGF) signaling pathways are essential for normal epicardial development, and the main goal of this proposal is to discover how PDGFs direct epicardial cell development and differentiation. This goal will be accomplished using epicardial-specific loss-of-function alleles of the PDGF receptors in the mouse.
The specific aims of this proposal are: 1) To determine the mechanism of PDGF receptor action in the initial development of the epicardium;2) To elucidate the requirement for PDGFR2 in coronary vascular smooth muscle cells and cardiac fibroblasts;and 3) To determine if PDGFR1 signaling is required for fibroblast development and function within the heart. Understanding the mechanisms of PDGF receptor function in the epicardium and epicardial derived cells will provide important insights into the signaling mechanisms governing epicardial cell biology and potentially reveal signaling pathways that could be manipulated to control fibrosis and direct angiogenesis after cardiac injury.

Public Health Relevance

Cardiac fibrosis and impaired coronary artery function are two major features of heart disease, but few drugs or therapies have been identified that act upon the cells responsible for these problems. The goal of this research is to identify signals that can alter the formation and function of these cell types. Manipulation of these signals could improve the outcomes of cardiac injury. The success of these studies will provide information to advance the treatments used in repairing damaged hearts and reducing fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074257-06
Application #
7787511
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
6
Fiscal Year
2010
Total Cost
$392,500
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Kuwabara, Jill T; Tallquist, Michelle D (2017) Tracking Adventitial Fibroblast Contribution to Disease: A Review of Current Methods to Identify Resident Fibroblasts. Arterioscler Thromb Vasc Biol 37:1598-1607
Ivey, Malina J; Kuwabara, Jill T; Pai, Jonathan T et al. (2017) Resident fibroblast expansion during cardiac growth and remodeling. J Mol Cell Cardiol 114:161-174
Pinto, Alexander R; Ilinykh, Alexei; Ivey, Malina J et al. (2016) Revisiting Cardiac Cellular Composition. Circ Res 118:400-9
Swonger, Jessica M; Liu, Jocelyn S; Ivey, Malina J et al. (2016) Genetic tools for identifying and manipulating fibroblasts in the mouse. Differentiation 92:66-83
McCarthy, Neil; Liu, Jocelyn S; Richarte, Alicia M et al. (2016) Pdgfra and Pdgfrb genetically interact during craniofacial development. Dev Dyn 245:641-52
Ivey, Malina J; Tallquist, Michelle D (2016) Defining the Cardiac Fibroblast. Circ J 80:2269-2276
Kanisicak, Onur; Khalil, Hadi; Ivey, Malina J et al. (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun 7:12260
Ten Freyhaus, Henrik; Berghausen, Eva M; Janssen, Wiebke et al. (2015) Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension. Arterioscler Thromb Vasc Biol 35:1236-45
Vicente-Steijn, Rebecca; Scherptong, Roderick W C; Kruithof, Boudewijn P T et al. (2015) Regional differences in WT-1 and Tcf21 expression during ventricular development: implications for myocardial compaction. PLoS One 10:e0136025
Moore-Morris, Thomas; Tallquist, Michelle D; Evans, Sylvia M (2014) Sorting out where fibroblasts come from. Circ Res 115:602-4

Showing the most recent 10 out of 27 publications