PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. IPF is characterized by fibroblast and myofibroblast foci and excessive accumulation of extracellular matrix (ECM) proteins. IPF is prevalent among the Veteran population. Myofibroblast differentiation is thought as one of the responsible mechanisms for excessive ECM protein production and accumulation, leading to progressive fibrotic lesions in lung. It is important to understand the molecular mechanisms that are responsible for myofibroblast activation in IPF. Tristetraprolin (TTP) is a major regulator of gene expression and modulates mRNA stability. The preliminary data demonstrate that TTP function is impaired in IPF. We speculate that impaired TTP function likely results in a dysregulated regulation system of gene expression, and consequently leads to pathological conditions. This proposal aims to investigate the role of TTP as a break to limit fibrotic response and lung fibrosis. It is important to understand the molecular mechanism leading to increased pro-fibrotic response in IPF. The preliminary data demonstrate that TTP regulates ECM protein expression and signaling that are important for myofibroblast differentiation and functions, and gain of TTP decreases ECM protein expression and signaling, and myofibroblast differentiation in IPF lung fibroblasts. We hypothesize that impaired TTP fosters a ‘pro-fibrotic ECM niche’, fueling cell-matrix interaction and signaling that increases myofibroblast differentiation and fibrotic responses. This proposal aims to define the role of TTP in myofibroblast differentiation and lung fibrosis, examine the molecular mechanism involved, determine the impact of impaired TTP function on ECM production and accumulation, and the role of TTP in fibrogenesis and fibrotic remodeling in vivo. Completion of this project will provide new insight about the mechanisms responsible for the development of pulmonary fibrosis and serve the goal to develop more effective therapy for IPF patients.