This R01 application will investigate a novel signaling pathway, the Hippo pathway, in mammalian heart regeneration. The long-term goal is to develop new treatments for patients with heart failure by generating new cardiomyocytes in the adult heart. The objectives of this application are to gain insight into molecular properties of cardiac tissue that are regulated by Hippo signaling. The central hypothesis is that Hippo signaling is a negative regulatory pathway that prevents cardiomyocyte regeneration in the adult mammalian heart.
The specific aims are to determine whether the Hippo and Wnt pathways regulate adult heart regeneration in a manner similar to the interaction in heart development; to determine whether the sumoylation post-translation modification is an important mechanism in Yap regulation; and to determine whether Hippo functions in the context of a chronic scar after myocardial infarction. The project is conceptually and technically innovative. Concepts to be tested include new ideas in cardiomyocyte biology and cutting edge genome editing technologies to address hypotheses. The significance is high because there are no treatments for heart failure due to cardiomyocyte loss. Devising ways to generate new cardiomyocytes is highly significant.

Public Health Relevance

Heart failure due to cardiomyocyte (heart cell) loss and pump dysfunction after ischemic heart disease is the leading cause of death in the United States. We strive to facilitate cardiac regeneration after heart damage to improve survival rates. The limited ability of adult heart cells (cardiomyocytes) to divide and multiply negatively impacts the capacity of the heart to repair itself after acute damage. Our goal is to devise new methods to promote heart repair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL127717-01A1
Application #
9029160
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Wang, Lan-Hsiang
Project Start
2016-01-15
Project End
2019-12-31
Budget Start
2016-01-15
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$507,968
Indirect Cost
$190,488
Name
Texas Heart Institute
Department
Type
DUNS #
086987831
City
Houston
State
TX
Country
United States
Zip Code
77225
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Leach, John P; Heallen, Todd; Zhang, Min et al. (2017) Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550:260-264
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