Primary Sclerosing Cholangitis (PSC) is a chronic immune-mediated cholestatic liver disease that can progress to cirrhosis, end-stage liver disease, cancer and need for liver transplantation. Even though PSC starts with progressive fibrotic injury of the biliary tree, the resultant bile acid injury to the hepatocytes is important in diseases progression. Unfortunately, there is currently no effective medical treatment for patients with PSC. Activating transcription factor 4 (ATF4) is a master transcription factor that regulates many biological processes, such as endoplasmic reticulum (ER) stress, oxidative stress, autophagy and apoptosis that are involved in the pathogenesis of cholestatic liver injury. ATF4 level is reported to be significantly decreased in the intestinal mucosa from patient with Crohn’s diseases and ulcerative colitis, which are disease conditions closely related with PSC. Our preliminary data demonstrated that ATF4 expression was significantly decreased in the multi drug resistance 2 gene knockout (Mdr2(-/-)) mouse model of PSC and other murine models of cholestatic liver injury. The protective autophagy function is also reduced in the murine model of PSC. The central hypothesis is that hepatic ATF4 is protective in the pathogenesis of cholestatic liver diseases including PSC. The aim of the current proposal is to determine the role and regulatory mechanism of hepatic ATF4 in Mdr2(-/-) mice model of PSC. This study will likely identify novel therapeutic targets for drug development to treat patients with PSC and other cholestatic disorders.
|Effective start/end date||7/1/20 → 6/30/22|
- PSC Partners Seeking a Cure (AGMT 5/15/20)