Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease. There is no effective therapy that alters mortality or disease progression in IPF so far. ZFP36 is an mRNA-destabilizing protein. ZFP36 expression is significantly decreased in IPF. The role of ZFP36 in lung fibrosis, and the functional consequence of pathologic ZFP36 downregulation in fibrotic reactions, are completely unknown. Our preliminary data indicate that ZFP36 negatively regulates the expression of multiple pro-fibrotic mediators through a post-transcriptional regulation mechanism. Decreased ZFP36 expression results in a defective/failed feedback loop to control the pro-fibrotic reactions in IPF lung fibroblasts. Importantly, preliminay data demonstrate that ZFP36-deficient mice have increased lung fibrosis when compared to wild-type mice in response to bleomycin. We hypothesize that ZFP36 functions as a negative regulator of lung fibrosis and pro-fibrotic reactions through a post-transcriptional regulation mechanism. We further hypothesize that ZFP36 reduction in IPF results in unbridled expression of pro-fibrotic mediators due to prolonged stability of pro-fibrotic mediator mRNAs. To test our hypothesis, three specific aims are proposed.
Aim 1 seeks to define the role of ZFP36 in control of the expression of pro-fibrotic mediators and to determine the post-transcriptional mechanism involved.
Aim 2 will determine the functional consequence of ZFP36 deficiency in the development of lung fibrosis in vivo, and explore the mechanisms by which ZFP36 controls lung fibrosis in vivo.
Aim 3 seeks to determine the molecular mechanism of pathologic ZFP36 downregulation and its consequences in IPF lung fibroblasts. The findings will define the novel role of ZFP36 as a negative regulator of lung fibrosis, and provide new insights about the molecular mechanism by which ZFP36 deficiency promotes pro-fibrotic responses and lung fibrosis. This work supports our long-term goal to utilize new knowledge to develop novel therapeutic approaches to inhibit the persistent fibrotic reactions in IPF.
Idiopathic pulmonary fibrosis (IPF) is a devastating fibrotic lung disease with poor outcome. Findings from this project are important to understand the molecular mechanism involved and to develop novel therapeutic intervention for IPF.
