Cholestatic liver diseases are highly prevalent causes of progressive liver disease in the United States and are a common indication for liver transplantation. Unfortunately, current medical therapies are not curative and frequently do not prevent disease progression. Over the past decade, the Unfolded Protein Response (UPR), an adaptive cellular response to Endoplasmic Reticulum (ER) stress, has been implicated in the pathogenesis of many liver diseases. However, the role of the UPR in hepatic bile salt injury and cholestatic liver injury remains poorly understood. We show preliminary data demonstrating that IRE1alpha/Xbp1 regulates cholestatic liver injury and the bile acid pool, and it is also regulated by the FXR and FGF15/19 bile acid signaling pathways. Therefore, we will determine the role of the IRE1alpha/XBP1 pathway in: A) cholestatic liver injury and; B) regulation of hepatic bile acid metabolism (Specific Aim 1). We will determine the regulation of the hepatic IRE1alpha/Xbp1s pathway of the UPR by FXR/SHP and FGF15/19 signaling (Specific Aim 2). Finally, i we will utilize murine models to determine the in vivo regulation of the IRE1alpha/XBP1 pathway by and FXR and FGF15/19 signaling (Specific Aim 3). While the proposal focuses on hepatic IRE1alpha/Xbp1 signaling, our long-term goal is to further develop a line of research characterizing the UPR signaling pathways that reduce liver injury and may serve as therapeutic targets for the treatment of cholestatic liver diseases.
|Effective start/end date||8/1/17 → 7/31/21|
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK093807-08)