Posttranscriptional Regulation of RNA Binding Proteins in Heart Failure

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Summary Heart failure is a major public heath issue worldwide and its morbidity and mortality are unacceptably high, and remains the leading cause of morbidity, mortality, and hospitalization among adults and the elderly. Given these clinical observations, development of new therapeutic targets is urgently required and understanding the molecular mechanisms responsible for heart failure development and progression is critically important to develop new therapeutic targets. For genes to produce their final functional products (proteins or non-coding RNAs), the RNA transcripts need to be extensively processed after transcription, including splicing, modification, transportation and translation. RNA binding proteins (RBPs) are important regulators in each step of the complex processes of RNA metabolism and are being recognized as emerging key players in the pathogenesis of heart failure. Although transcriptional changes have been extensively studied in the failing hearts, very little is known about the role of posttranscriptional events in the remodeling heart. In this proposal, we will systematically investigate the role of RNA binding protein 20 (RBM20) in the pathogenesis of heart failure. We hypothesize that RBM20 phosphorylation and mutations on phosphorylation sites alter the posttranscriptional process and lead to cardiac remodeling, and RBM20 isoforms and cofactors regulate fetal gene re-expression in adult heart to promote heart failure. To test the hypothesis, we have created mutation knock-in (KI) and double knockout mouse models to evaluate functional roles of posttranscriptional event changes in cardiac remodeling, and determine the genes and proteins affected by the posttranscriptional changes. KI mice will be used to evaluate the translational value with the inhibitor of nuclear transport for RBM20-meidated nucleo-cytoplasmic trafficking. Two specific aims are proposed in this proposal. 1) Determine the functional roles of RBM20 phosphorylation and genetic mutations on phosphorylation sites in the pathogenesis of heart failure; 2) Determine the molecular/cellular mechanisms of RBM20 mediated posttranscriptional regulation of heart failure through cofactors and RBM20 isoforms. The achievement of the proposed aims will gain new information regarding RBPs-mediated posttranscriptional regulation in the pathogenesis of heart failure and provide a new paradigm for the mechanistic study on genetic mutations- induced heart failure.