Myocardial infarction (MI) and its sequelae are a significant burden on healthcare infrastructure worldwide. The number of therapeutic agents that target the pathological response to myocardial infarction are limited, thus a broad understanding of the intrinsic cell survival mechanisms that are activated following infarction could have important implications for developing new strategies to treat MI patients. MicroRNAs are small regulatory nucleic acids that exhibit a robust influence on gene expression. Recently, microRNAs have been identified as integral components in the pathological response to myocardial infarction. Our long-term goal is to understand mechanisms of gene regulation that are activated shortly following acute myocardial infarction, and how such genetic regulation might affect cell survival. Specifically, we are interested in the role of microRNA-210, a hypoxia associated microRNA (miR), in the myocyte following infarction. MiR-210 is up-regulated in the infarcted heart within 24 hours and is induced in cultured cardiomyocytes by hypoxia. Constitutive over-expression of miR-210 in the adult mouse heart results in dilated cardiomyopathy and death within 4 weeks, possibly due to metabolic derangement. First, we aim to understand the pathways that are important for the induction of miR-210 in response to hypoxia. We will use transgenic reporter mouse lines to delineate the genomic regions that govern miR-210 expression, as well as in vitro assays to test for transcriptional regulators of miR-210. We will then study the effects of miR-210 on metabolism in transgenic mice and in cultured cardiomyocytes. Last, we will generate a conditional knockout mouse for miR-210 in order to study its function following MI in vivo. This collection of studies will provide insight into the molecular response to myocardial infarction and possibly identify novel points of therapeutic intervention. )
Greater than 1 million Americans suffer from a heart attack(myocardial infarction) each year, and many of these patients will eventually progress to heart failure. We aim to study the cardiac response to myocardial infarction at the molecular level, with the hope that the insight we gain can be used to develop treatments that prevent injury and mortality that result myocardial infarction.
|Quiat, Daniel; Olson, Eric N (2013) MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. J Clin Invest 123:11-8|
|Quiat, Daniel; Voelker, Kevin A; Pei, Jimin et al. (2011) Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6. Proc Natl Acad Sci U S A 108:10196-201|