The number one cause of death in the US and developed world is heart failure consequent to infarct. Primary goals for cardiac repair are to replace cardiomyocytes, stabilize neovascularization, and prevent scar formation. In contrast to mammalian myocardium, zebrafish heart regenerates post-injury by myocyte replacement, neoangiogenesis, and resolution of scar tissue. Regeneration of zebrafish heart requires activation of cells which outline the heart, the epicardium, but how epicardium contributes to regeneration is not known. During mouse heart development, epicardium gives rise to a number of cell types, including vascular support cells and cardiomyocytes. Although these data suggest the potential of epicardium to contribute cells for cardiac repair, adult epicardial cells lose the ability to become cardiomyocytes. Epicardial lineages also give rise to cardiac fibroblasts/myofibroblasts, which contribute to scarring post-infarct. Hepatic stellate cells (HSCs) share an embryonic origin with epicardial fibroblasts, and also contribute to fibrosis following acute liver injury. However, HSCs undergo senescence to promote scar resolution during liver regeneration. These findings suggest our goal, which is to achieve cardiac regeneration by promoting epicardial cells to adopt cardiomyocyte cell fates post-injury, and cardiac fibroblasts to undergo senescence to resolve scar formation. Toward this goal, we will generate new models of cardiac injury and new approaches for epicardial fate mapping to examine epicardial behavior post-injury in developing and adult mouse heart. We will identify mechanisms underlying the ability of embryonic epicardial cells to adopt cardiomyocyte cell fates, and apply this knowledge to promote adult epicardial cells becoming cardiomyocytes post-injury. We will gain insights into senescence behavior of cardiac fibroblasts, to activate these pathways in an injury setting. If successful, results of these studies will define new therapeuti

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1HL117649-05
Application #
8539072
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (02))
Program Officer
Adhikari, Bishow B
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$728,066
Indirect Cost
$256,826
Name
University of California San Diego
Department
None
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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