Grant: Operating Grant

The normal function of human proteins is to support the healthy growth of cells. Importantly, certain proteins can also play important roles in the infectious cycles of human pathogens and the development of cancer through abnormal participation in other processes. One such family of proteins includes the La protein and La-related proteins. La proteins normally play critical roles in the processing of cellular RNAs that are required for normal gene expression, in part by ensuring that these RNAs fold into the correct form required for their function. However, a large body of evidence also indicates that many human viruses, including hepatitis C, hepatitis B and HIV, depend on La function for productive viral infections. Notably, abnormal La activity has been observed in the livers of human patients infected with hepatitis C. Furthermore, abnormal La function has also been implicated in the irregular expression of important genes in leukemia and cervical cancer. While we have an increasingly strong understanding of the role La proteins plays in RNA processing in normal cells, knowledge of the mechanisms by which La proteins abnormally contribute to human disease states is severely lacking. This proposal aims to target this knowledge gap. Major research questions that we hope to address include: how do La proteins bind and recognize different types of RNA targets (i.e. its normal, cellular RNAs vs. viral RNAs)? What specific function of La proteins is required in their abnormal associations with disease related RNAs? Finally, how do the more recently discovered La-related proteins, which have also been implicated in viral pathogenesis and cancer, fit into this picture? By enhancing our understanding of the contribution of this family to these disease states, the work outlined in this proposal aims to identify new targets for therapeutic intervention for a number of challenges to human health.