Primary Sclerosing Cholangitis (PSC) is a chronic liver disease that can progress to cirrhosis, end-stage liver disease and cancer. Unfortunately, there is currently no effective medical therapies for PSC, in part, due to our limited understanding of the pathogenesis of PSC. The unfolded protein response (UPR) is an adaptive cellular response to Endoplasmic Reticulum (ER) stress, a term used to describe a form of cellular stress that occurs due to an excess of misfolded or unfolded protein. The UPR has been shown to be important in many liver diseases, including viral hepatitis, fatty liver disease, metabolic liver disorders and genetic liver disorders. For the past decade, my laboratory’s primary line of investigation has focused on the role of the liver UPR in PSC and other forms of cholestasis liver disease. Recent clinical studies and murine studies over the past decade have demonstrated the importance of the UPR in PSC and cholestasis. The central hypothesis of our research is that hepatic UPR pathways are important in the pathogenesis of cholestatic liver disease. Our long-term goal is to develop novel therapies for cholestasis targeting IRE1/Xbp1, CHOP and other UPR pathways including PSC. The goals of the current proposal are to further develop and perform pre-clinical animal studies of UPR-based pharmacologic, genetic and nanoparticle-siRNA treatments for PSC using the MDR2-knockout (MDR2-/-) mouse model of PSC. We will utilize a pharmacologic and genetic approach to activate the hepatoprotective XBP1 pathway; and use a liver-specific HDL-like nanoparticle approach to silence the hepatic expression of the pro-apoptotic gene CHOP. If successful, these investigations will provide essential pre-clinical data that is required to translate this bench-to-bedside translational approach to develop UPR-based therapies for patients with Primary Sclerosing Cholangitis.
|Effective start/end date||11/1/21 → 10/31/23|
- PSC Partners Seeking a Cure (AGMT - 11/02/2021)
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