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 #
5R01HL115275-02
Application #
8517813
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
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$378,420
Indirect Cost
$140,420
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Mahmoud, Ahmed I; Porrello, Enzo R; Kimura, Wataru et al. (2014) Surgical models for cardiac regeneration in neonatal mice. Nat Protoc 9:305-11
Kocabas, Fatih; Zheng, Junke; Zhang, Chengcheng et al. (2014) Metabolic characterization of hematopoietic stem cells. Methods Mol Biol 1185:155-64
Puente, Bao N; Kimura, Wataru; Muralidhar, Shalini A et al. (2014) The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157:565-79
Zhang, Cheng Cheng; Sadek, Hesham A (2014) Hypoxia and metabolic properties of hematopoietic stem cells. Antioxid Redox Signal 20:1891-901
Mahmoud, Ahmed I; Kocabas, Fatih; Muralidhar, Shalini A et al. (2013) Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497:249-53
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