MicroRNAs, cardiac development and function MicroRNAs (miRNAs) are a class of small regulatory RNA molecules found in most organisms. Emerging evidence has established that miRNAs play important regulatory roles, mainly through degrading target messenger RNAs (mRNAs) and/or inhibiting translation of protein-coding mRNAs in a variety of biological processes, including cell proliferation, differentiation and survival. miRNAs are also implied in many human diseases, including cardiovascular disease. The discovery of miRNAs and their potential biological function in regulating gene expression opened a completely new field to investigate how miRNAs participate in "classical" gene expression pathways. To date, more than 1,000 miRNAs have been identified in humans;however, the molecular mechanisms and the in vivo functions of most miRNAs remain unknown. We found that miR-208a regulates cardiac hypertrophic growth, in part, by modulating the expression level of the key homeobox transcription factor Hop and stress responsible heat shock protein 70 (Hsp70). We also showed that a cardiac-specific RNA helicase Csm participates in miRNA functional pathways. Disruption of Csm in zebrafish impairs cardiac morphogenesis owing to a suppression of cardiomyocyte proliferation. Conversely, transgenic overexpression of Csm in murine hearts led to cardiac hyperplasia and cardiomyocyte overproliferation, confirming the essential role of Csm in multiple vertebrate species. The overall goal of this proposal is to define the biological function and the molecular mechanisms of miRNAs in the heart. Our central hypothesis is that miRNAs are components of the molecular circuitry that controls mammalian cardiovascular development and function. More specifically, based on our preliminary observations, we will test our hypothesis that miR-208a regulates the expression level of Hop and Hsp70 to convey stress response in cardiomyocytes. We further hypothesize that Csm mediates miRNA homeostasis in cardiomyocytes to regulate their proliferation. We present three integrative aims to test our hypothesis:
Aim #1. To study the in vivo function of cardiac-specific miR-208a in the heart and the molecular pathways regulated by this miRNA.
Aim #2. To investigate the molecular events mediated by Csm, a cardiac-specific RNA helicase, in miRNA pathway.
Aim #3. To define the role of Csm in cardiac development and cardiomyocyte proliferation.

Public Health Relevance

MicroRNAs, cardiac development and function relevance congenital heart disease represents one of the most common classes of birth defects in humans. Cardiovascular disease is the leading cause of death in United States. Our studies will provide important insights into the molecular mechanisms by which miRNAs control mammalian heart development and cardiac gene expression. The molecular strategies we uncover in these studies will help define the ontogenesis of human congenital heart defects (CHD) with potential broader implications for understanding the pathophysiology of cardiac disease and failure in humans.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Schramm, Charlene A
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Children's Hospital Boston
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