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 PDGFR? in coronary vascular smooth muscle cells and cardiac fibroblasts;and 3) To determine if PDGFR? 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 #
5R01HL074257-09
Application #
8511775
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2009-04-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
$421,965
Indirect Cost
$141,165
Name
University of Hawaii
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Zhao, Chen; Guo, Hua; Li, Jingjing et al. (2014) Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation. Development 141:281-95
Moore-Morris, Thomas; Tallquist, Michelle D; Evans, Sylvia M (2014) Sorting out where fibroblasts come from. Circ Res 115:602-4
Wood, Michelle A; Acharya, Asha; Finco, Isabella et al. (2013) Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development 140:4522-32
Neubauer, Bjoern; Machura, Katharina; Rupp, Verena et al. (2013) Development of renal renin-expressing cells does not involve PDGF-B-PDGFR-* signaling. Physiol Rep 1:e00132
Baek, Seung Tae; Tallquist, Michelle D (2012) Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation. Development 139:2040-9
Chhabra, Akanksha; Lechner, Andrew J; Ueno, Masaya et al. (2012) Trophoblasts regulate the placental hematopoietic niche through PDGF-B signaling. Dev Cell 22:651-9
Smith, Christopher L; Baek, Seung Tae; Sung, Caroline Y et al. (2011) Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ Res 108:e15-26
Caglayan, Evren; Vantler, Marius; Leppänen, Olli et al. (2011) Disruption of platelet-derived growth factor-dependent phosphatidylinositol 3-kinase and phospholipase C? 1 activity abolishes vascular smooth muscle cell proliferation and migration and attenuates neointima formation in vivo. J Am Coll Cardiol 57:2527-38
Wu, Mingfu; Smith, Christopher L; Hall, James A et al. (2010) Epicardial spindle orientation controls cell entry into the myocardium. Dev Cell 19:114-25
Zhou, Li; Takayama, Yoshiharu; Boucher, Philippe et al. (2009) LRP1 regulates architecture of the vascular wall by controlling PDGFRbeta-dependent phosphatidylinositol 3-kinase activation. PLoS One 4:e6922

Showing the most recent 10 out of 13 publications