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The role of Eukaryotic Translation Elongation Factor 1 Alpha 2 in cardiac function and disease

Institution: University of California, San Diego
Investigator(s): Ju Chen,
Award Cycle: 2019 (Cycle 29) Grant #: T29IP0304 Award: $498,058
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: High Impact Pilot Award

Initial Award Abstract
Cardiovascular disease (CVD) is the leading cause of death in the United States and cigarette smoking significantly increases the risk of developing CVD. However, the underlying reason for this increased susceptibility observed in smokers is still unclear. Heart development and maintaining healthy heart function require a well-orchestrated system whereby proteins are synthesized. Smoking has been shown to suppress protein synthesis, but exact mechanisms underlying regulation of protein synthesis in the contractile cells of the heart, cardiomyocytes (CMs), are not very clear.

Protein synthesis is mediated by the tightly synchronized coordination of many factors. One of these factors is named eukaryotic translation elongation factor 1A (eEF1A). EEF1A has two distinct isoforms, eEF1A1 and eEF1A2. While eEF1A1 is expressed throughout the body, eEF1A2 expression is limited to skeletal muscle, heart, brain, and the spinal cord, suggesting that eEF1A2 has tissue-specific functions. A recent study identified that patients carrying a mutation in their eEF1A2 gene exhibit developmental delays and a heart disease termed dilated cardiomyopathy, ultimately leading to death in early childhood. Moreover, our preliminary data shows that the protein level of eEF1A2 is significantly decreased in the failing hearts of mice. However, the specific role of eEF1A2 in the heart remains unknown.

To investigate the role of eEF1A2 in the heart, we generated a mouse model that will allow us to understand the role of eEF1A2 in both developing and adult CMs, by deleting eEF1A2 at early and adult stages, respectively. Characterization of protein synthesis changes in the hearts of these mice will help us to identify the specific subset of proteins critical for heart development and function controlled by eEF1A2. Our findings from this proposal will significantly impact our general understanding of the molecular basis of protein synthesis in heart development, function, and disease. Ultimately, this will bring us closer to our long-term goal of identifying new therapeutic approaches for treatment of heart disease and prevent development of heart failure in the smoking population.