Heart failure is a costly and deadly disease, affecting over 23 million patients worldwide, 5.8 million patients in America, half of which die within 5 years of diagnosis. In addition, heart failure costs the US government over 39 billion Dollars in health care costs annually. Systolic heart failure, resulting from cardiomyocyte loss, is the leading cause of heart failure. At the core of the pathophysiology of heart failure is the inabilit of the adult heart to regenerate. Instead, lost myocytes are replaced by fibrous tissue, which results in progressive remodeling, dilatation, and further contractile dysfunction. We recently discovered that the newborn mouse heart is able completely regenerate following injury, primarily through proliferation of pre-existing cardiomyocytes. Moreover, we identified Meis1 as a key regulator of mammalian cardiomyocyte proliferation post-natally. Our preliminary results using targeted Meis1 deletion in cardiomyocytes indicate that loss of Meis1 results in robust cardiomyocyte proliferation in the adult heart. Finally, we identified the cell cycle inhibitors p1 and p21 as potential targets for Meis1 in cardiomyocytes. Therefore, we hypothesize that Meis1 regulates cardiomyocyte proliferation through transcriptional activation of p16 and p21. We will utilize Meis1 loss of function and gain of function mouse models, as well as an array of in vivo and in vitro techniques to address this hypothesis. Ultimately, we hope to exploit our understanding of the role of Meis1 in cardiomyocyte proliferation to uncover new disease mechanisms and therapeutic approaches for cardiovascular diseases.

Public Health Relevance

Heart failure is a costly and deadly disease affecting over 5 million patients in America, half of which die within 5 years of diagnosis. The aim of this project is to determine how to make adult heart cells divide. This can potentially lead to a cure for heart failure by uncovering new strategies for regeneration of the adult heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL115275-03
Application #
8710336
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Adhikari, Bishow B
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Canseco, Diana C; Kimura, Wataru; Garg, Sonia et al. (2015) Human ventricular unloading induces cardiomyocyte proliferation. J Am Coll Cardiol 65:892-900
Xiao, Feng; Kimura, Wataru; Sadek, Hesham A (2015) A hippo ""AKT"" regulates cardiomyocyte proliferation. Circ Res 116:3-5
Sen, Shawdip; Sadek, Hesham A (2015) Neonatal heart regeneration: mounting support and need for technical standards. J Am Heart Assoc 4:e001727
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Zhang, Cheng Cheng; Sadek, Hesham A (2014) Hypoxia and metabolic properties of hematopoietic stem cells. Antioxid Redox Signal 20:1891-901
Kimura, Wataru; Muralidhar, Shalini; Canseco, Diana C et al. (2014) Redox signaling in cardiac renewal. Antioxid Redox Signal 21:1660-73
Porrello, Enzo R; Mahmoud, Ahmed I; Simpson, Emma et al. (2013) Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A 110:187-92

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