Therapeutic applications of miRNAs in myocardial infarction and cardiac regeneration The long-term goal of our study is to understand the cellular and molecular mechanisms that control the proliferation of heart cells (cardiomyocyte). We propose to use microRNAs, a class of small non-coding RNAs, as molecular tools to explore the molecular mechanisms of cardiomyocyte proliferation and cardiac regeneration. We hypothesize that miR-19a/miR-19b are key components of a molecular circuit that controls cardiomyocyte proliferation and cardiac regeneration. The overall goal of this study is to test the therapeutic potential of these miRNAs in repairing damaged hearts. We present two focused yet integrative aims to test our hypothesis:
Aim #1. To test the hypothesis that miR-19a/miR-19b plays a key role in cardiac regeneration that can serve as a therapeutic target to repair infarcted hearts.
Aim #2. To define the molecular mechanism by which miR-19a/miR-19b repress their targets to protect the damaged hearts. This study will uncover novel components and molecular pathways for the control of cardiomyocyte proliferation and cardiac regeneration.

Public Health Relevance

Therapeutic applications of miRNAs in myocardial infarction and cardiac regeneration Ischemic heart disease resulting in myocardial infarction (MI) and heart failure is the leading cause of morbidity and mortality in the United States. More than 1 million people suffer heart attack each year in the United States. Cardiomyocytes in adult human hearts are terminally differentiated cells that have exited from the cell cycle and lost most of their proliferative capacity. Death of mature cardiomyocytes in pathological cardiac conditions (e.g. heart attack) and the lack of sufficient regenerative capacity of adult hearts are primary causes of heart failure and mortality. The overall goal of our investigation is to understand the functional role of miR- 19a/19b in cardiomyocyte proliferation and cardiac regeneration as well as its therapeutic potential in repairing damaged hearts. We will test the efficiency and specificity of miRNAs in cardiac protection, utilizing well-established animal models of human myocardial infarction and heart failure and. Our studies will provide important insights into the molecular mechanisms by which miRNAs control myocyte proliferation, and cardiac regeneration in response to stress. The molecular strategies uncovered in these studies will help to define the ontogenesis of human heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125925-04
Application #
9619295
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, Renee P
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Ding, Jian; Lin, Zhi-Qiang; Jiang, Jian-Ming et al. (2016) Preparation of rAAV9 to Overexpress or Knockdown Genes in Mouse Hearts. J Vis Exp :
Naya, Francisco J; Wang, Da-Zhi (2016) (MYO)SLIDing Our Way Into the Vascular Pool of Long Noncoding RNAs. Arterioscler Thromb Vasc Biol 36:2033-4
Ding, Jian; Chen, Jinghai; Wang, Yanqun et al. (2015) Trbp regulates heart function through microRNA-mediated Sox6 repression. Nat Genet 47:776-83