PROTECTIVE ROLES OF miR-29a AND miR-18a IN LIVER FIBROSIS
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Date
2013-12-18
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Johns Hopkins University
Abstract
The research described in this dissertation highlights the need for clinical therapeutics for fibrosis, targeting fibrotic mechanisms and how miRNAs can be powerful modulators of fibrosis. miRNAs are 22 nucleotide long, post-transcriptional regulators of gene expression. We profiled miRNA expression changes in two different models of liver fibrosis and identified two different miRNAs which showed differential expression in fibrotic livers.
miR-29 family targets many proteins in the extracellular matrix and is downregulated during fibrosis in many organs. We developed a viral vector based delivery of miR-29 to replace lost miR-29 during fibrosis. Successful prevention and reversal of ongoing hepatotoxin mediated fibrosis was seen with hepatocyte-specific expression of the viral vector, illustrating the powerful anti-fibrotic role of miR-29. Our research supports and encourages industry interest in developing miR-29 based drugs, which takes us one step closer to alleviating distress of patients in the clinic.
Alcohol mediated fibrosis is a major health problem in the world and is the major cause contributing to the increased need for liver transplantation. We studied miR-18a, which is increased in alcohol and hepatotoxin mediated liver fibrosis. miR-18a expression is localized to cells in the same region as fibroblasts, which are the key responders in fibrosis. This miRNA targets components of TGFB signaling pathway and affects pro-fibrotic processes such as fibroblast migration and collagen production. miR-18a is downregulated by TGFB, illustrating that TGFB downregulates its own negative regulator, fine-tuning signaling activity. Combined, these results strongly suggest a protective role of miR-18a during liver fibrosis.
This work establishes a large body of knowledge about miRNAs and their roles in regulating fibrosis. We identified cell type specific expression and function of miRNAs within the liver that further confirms the need to look not only at whole tissue expression but also in different individual cells. We have highlighted the role of miRNAs in regulating and therapeutically treating liver fibrosis and hope that clinical drugs of miRNAs would not be too far in the future.
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Liver fibrosis, miRNA, miR-29a, miR-18a, TGFB pathway