Research Projects

Human idiopathic pulmonary fibrosis (IPF) is characterized by epithelial injury, persistent myofibroblast phenotype and excessive deposition of extracellular matrix. The patient survival rate is 3 years after diagnosis. IPF remain the most prevalent health condition in India especially due rising environmental pollution, viral and bacterial infections. The development of IPF was highly dependent on thrombin-protease activated receptor 1 (PAR1) activity and its downstream signaling pathways. Exciting findings from my doctoral and post-doctoral studies reveal that endothelial protein C receptor (EPCR: a common receptor for many blood coagulation proteins including APC, FVIIa and FXa) is expressed on lung epithelial cells and plays a cardinal role in the development of lung fibrosis. The EPCR-/- mice manifest attenuated lung injury, inflammation, and protected from pleural fibrosis. EPCR-induced signaling is highly dependent upon the cooperation with PAR1 signaling pathway. However, the precise role of EPCR in the pathogenesis of IPF is currently unknown. The activation of a transcription factors, NF-kB and c-Jun, are critical for inflammation and fibrosis in the lung. Our recent studies show that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) mediates PAR1-induced c-Jun and NF-kB activation via its scaffolding and proteolytic activities. However, the role of PAR1-MALT1 axis in the pathogenesis of IPF is not known. It has been recently shown that polyubiquitination of PAR1 is essential for its inflammatory signaling. Similarly, polyubiquitination of MALT1 is essential for its stability and signaling. Currently, it is unknown whether PAR1 activation leads to MALT1 ubiquitination, and the role of such modifications of MALT1 in the development of lung fibrosis remains obscure. Therefore, understanding the role of PAR1-MALT1 axis in the lung fibrosis will lead to development of novel therapeutics targeting EPCR-PAR1-MALT1 pathway. The hypothesis of this proposal is that 1) activation of MALT1 via EPCR or PAR1 signaling in the lung epithelial cells is essential for the development of fibrosis in murine models of airway remodeling by promoting epithelial to mesenchymal transition (EMT), 2) MALT1 mediates PAR1 downstream signaling, via ubiquitination coordinated linker phosphorylation of c-Jun and NF-kB, resulting in enhanced expression of mesenchymal genes, critical to PAR1-induced fibrosis. This project also ventured to test the efficacy of different class of inhibitors such EPCR blockers (biological therapy) or PAR1/MALT1 ubiquitin blocker (small molecule) or MALT1 specific inhibitors (small molecules) in preclinical settings of IPF in the mice. The outcome of our study, which is based on cell culture and preclinical mouse models, will provide a better understanding of the new molecular signals that lead to lung fibrosis resulting in the development of new therapeutics to limit IPF.