Microtubule-mediated tRNA localization in cardiac homeostasis and hypertrophy

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PROJECT SUMMARY In response to hemodynamic demands faced by the heart, cardiomyocytes adapt and remodel primarily through changes in myocyte thickness or length. In conditions like cardiovascular exercise, changes in physiological hypertrophy can aid in improving cardiac function. However, in conditions of prolonged elevated blood pressure, heart rate, and excessive weight gain, pathological hypertrophy occurs and ultimately can contribute to heart failure. Changes in cardiomyocyte growth and atrophy that subsequently impact physiological and pathological cardiac remodeling are dictated by changes in protein synthesis. And while there is significant progress in understanding the transcriptional and translational changes that mediate maladaptive cardiac remodeling, little is known about the changes in the most abundant noncoding RNAs that link these two processes: transfer RNAs (tRNA). Outside of the notion that Polymerase III activity, which is required for tRNA transcription, increases in response to cardiac pressure overload, almost completely nothing is known about how alterations in tRNA transcription, transport, and localization impact sites of protein synthesis and, ultimately, cardiac remodeling. Considering that heart failure and the preceding changes in myocyte size contribute to the majority of deaths in the United States, there is an unmet need for new therapies that target malignant protein synthesis in pathological cardiac hypertrophy. Hence, this need may be met by identifying new regulating transcription and translational control from a novel tRNA-centric view. In this proposal, we will examine the relationship between tRNA transcription, transport, and localization in cardiac homeostasis and hypertrophy. We have identified that tRNAs, which are believed to primarily rely on passive diffusion for appropriate localization, require the microtubule network for proper localization in the heart. We hypothesize that pathological and physiological hypertrophy induce different changes in tRNA transcription; but that both types of growth require motor protein-mediated active transport of tRNAs along the microtubule network to facilitate necessary increases in protein synthesis for cardiomyocyte growth. We will test our hypothesis by carrying out the following aims: (1) To determine the role of microtubules in tRNA trafficking and localization in the cardiomyocyte. (2) To characterize the localization and expression of mammalian tRNAs during cardiac remodeling. (3) To identify the proteins that facilitate tRNA trafficking in cardiomyocytes. This work will be carried out in the laboratory of Dr. Benjamin Prosser, an expert on microtubules, cardiomyocyte mRNA trafficking, and cardiac remodeling. Successful completion of this work will have the positive impact of defining how changes in tRNA transcription, localization, and trafficking impact cardiac homeostasis and hypertrophy and thus result in the potential new strategies that target heart failure through the regulation of maladaptive protein synthesis and compromised cardiac cell size.