RNA binding proteins in atherosclerosis

PROJECT SUMMARY Regulation of RNA biogenesis and turnover is central to the maintenance of cholesterol homeostasis and atherosclerosis development. More recently, we have come to appreciate that chemical modifications on RNA can profoundly dictate transcript fate. N6-methyladenosine methylation (m6A) is the most common RNA modification in mammalian cells. It is now established that m6A plays a critical role in cellular differentiation, organismal development, and cancer transformation. However, there is limited knowledge of the impact of RNA modifications on atherosclerosis pathways. The overarching goal of this proposal is to define the role and mechanisms of chemical modifications on RNA in atherosclerosis. Our recent studies and other abundant preliminary data, nominate m6A as a critical modulator of atherosclerosis risk factors and lesion development. In aim 1, we use genetic perturbations and vector-transduced models to investigate the importance of m6A in the control of serum cholesterol, and low-density lipoprotein uptake and test an RNA modification-based therapeutic strategy. In aim 2, we define how m6A in myeloid cells regulates cellular responses within lesions. Our assembled group of multidisciplinary scientists will work together to investigate this new layer in gene regulation. We anticipate that our proposed studies will provide important insights as to how RNA modifications impact cardiovascular health and disease and offer a provocative framework for new avenues in mitigating heart disease.