Investigation of the functional and molecular mechanism of RNA-binding protein PCBP1 in the heart

Abstract

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling, generally accompanied by exercise intolerance and skeletal muscle abnormalities. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling and function remains poorly understood. Poly(C)-binding proteins (PCBPs) are known as RNA-binding proteins that play important roles in gene expression via their ability to bind poly(C) regions. They are involved mainly in various posttranscriptional regulations (e.g., mRNA stabilization or translational activation/silencing). PCBP1 in particular acts at multiple levels in the expression process: as a translational repressor, a transcriptional coactivator, and as a regulator of RNA splicing. However, the role of PCBP1 remains to be further determined in the heart. Here, we plan to investigate the functional and molecular mechanism of RNA-binding protein PCBP1 in the heart. For a better characterization of PCBP1, we will performer in silico analysis by look into the PCBP1 locus and examine the expression of the putative long noncoding RNA, map the interaction domains and potential PCBP1 binding RNAs. We will evaluate the expression of human PCBP1 genes in diseased heart samples and the expression of PCBP1 (mRNAs and proteins) in MDX mice (heart and skeletal muscle). We will generate the cardiac specific PCBP1-KO mice to evaluate the PCBP1 involvement on cardiac function and remodeling. After this, we will study molecular mechanisms by downstream genes/pathway in these animals. Clearly the identification of additional binding targets and delineation of corresponding control mechanisms and effector pathways will establish highly informative models for further exploration.