Research Projects

Hepatic fibrosis is an integral step in the progression of chronic liver disease, ultimately leading to cirrhosis and hepatocellular carcinoma. Indian liver disease burden constituted about 18.3% of total two-million global liver disease related deaths. Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix (ECM) resulting from chronic liver injury. Activation of hepatic stellate cells leads to trans-differentiation into fibrogenic myofibroblasts, representing one of the central drivers of fibrosis in experimental and human liver injury. Current evidence suggests a prominent role for endoplasmic reticulum stress (ER) and activation of the unfolded protein response (UPR) in fibrotic conditions affecting the liver and other organs. ER stress enhances the susceptibility of liver structural cells to pro-fibrotic stimuli, suggesting that ER stress facilitates fibrotic remodeling. Overall, upon acute or chronic injury, the liver undergoes repair program accompanied by an inflammatory response and accumulation of extracellular matrix. Although prevention or reversal of HSC activation has been claimed as a potential approach to attenuate liver fibrosis, currently there is no effective approach to inhibit HSCs activation. Moreover, the underlying basis of HSC activation in pathological conditions is poorly understood. Despite the importance of HSCs in the morbidity of liver diseases, the exact contribution of ER stress to HSCs and its relation to the progression of liver fibrosis needs to be further investigated. We have obtained preliminary evidence indicating that ER stress is one of the major and earliest responses on a model of liver fibrosis, which is accompanied by clear signs of proteostasis impairment in vivo. Based on all this evidence, here we propose to define the significance of UPR transducer signaling to liver fibrosis in human HSCs and its possible relation to their differentiation and ECM secretory output. To accomplice our aims, we will use a loss of function approach through genetic (CRISPR/CAS) and pharmacological manipulation. Hypothesis: UPR signaling enhances the folding and secretory capacity of the ER through their downstream transcriptional factors promoting HSC activation and enrichment of ECM secretory output. General aim: To determine the contribution of the UPR signaling in HSCs activation and consequential liver fibrogenesis. This proposal represents a systematic attempt to better understand the specific role of ER stress to HSCs activation at the functional level and subsequent progression of liver fibrosis and its relation to collagen biology. Thus, this research proposal has the potential to provide relevant understanding of the cellular and molecular basis of liver injury and the future development of intervention strategies to mitigate the disease state.