- Warner Fibroproliferative diseases, such as pulmonary fibrosis, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, to name a few, are a leading cause of morbidity and mortality in the world and can affect all tissues and organ systems. A key step in the synthesis of collagen is the transport of mRNA from the nucleus to the endoplasmic reticulum, where it is translated, hydroxylated, and eventually exported to the cell membrane through interactions with multiple chaperone proteins. Intercepting the mRNA molecule from the nucleus, or stopping transport of mutant collagen mRNA to the ER could provide a targeted therapy in cases of excessive or inappropriate collagen synthesis. Our long- term goal is to understand the role that LARP6 plays in transport of collagen mRNAs so that we can target this interaction to prevent fibrotic disease progression. The overall objective of this proposal is to understand the molecular mechanisms that drive LARP6/mRNA interactions. Our central hypothesis is that LARP6 utilizes conformational selection in the recognition and discrimination of collagen mRNAs. We further hypothesize that dynamic sampling of the tandem arrangement of the La and RRM domains allows LARP6 to accommodate a diverse set of mRNA ligands. A logical extension of this hypothesis is that mRNA ligands also may also have adapted structure and/or dynamics that in turn guide selection by LARP6. An understanding of LARP6-mediated mRNA transport will lead to the identification of novel therapeutic targets that can mitigate fibroproliferative disease.
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