The Role of Vitamin D Receptor in Liver Fibrosis

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DESCRIPTION (provided by applicant): The candidate is a junior researcher with considerable experience in studying hepatic stellate cells (HSCs), liver fibrosis and gene regulation. However, to transition into a completely independent translational investigator, the candidate needs a period of additional supervised training. The NIDDK K01 award will enable the candidate to achieve this objective through a combination of academic coursework, didactic training, focused symposiums/conferences, and implementation of the proposed research project. The project will be carried out in the Gene Expression Laboratory at the Salk Institute for Biological Studies which provides a scientifically vibrant and inspiring environment and well-established state-of-the-art research facilities ideally suited to study human disease such as tissue fibrosis. In this regard, HSCs have been recognized as a pivotal regulator of liver fibrosis However, their role in mediating pro-inflammatory response during liver fibrosis remains poorly defined. Recent reports identified vitamin D receptor (VDR) in HSCs as an endocrine checkpoint for wound healing response in liver and VDR knockout mice develop spontaneous liver inflammation and fibrosis. Preliminary studies indicate that VDR is an important modulator of pro-inflammatory response in HSCs. Ligand-activated VDR represses a wide array of pro-inflammatory gene expression in HSCs through the direct genomic crosstalk with NF-κB and Vdr-deficient HSCs exhibit a spontaneous pro- inflammatory response. The overall hypothesis of this proposal is that VDR plays a role in liver fibrosis by modulating pro-inflammatory response in HSCs. Functional genomics, biochemical, genetic, and pharmacological approaches will be used to determine the roles of VDR in modulating pro-inflammatory pathways in HSCs, which underlie the pathogenesis and progression of liver fibrosis and related chronic liver diseases: Aim 1 will characterize the role of VDR signaling in modulating pro-inflammatory response in hepatic stellate cells (HSCs). Aim 2 will examine the role of VDR signaling in modulating pro-inflammatory response during liver fibrosis. Aim 3 will examine the role of VDR signaling in chronic liver diseases such as non- alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The ultimate goal of these investigations is to gain novel insights into the pathophysiology of HSCs to better understand the mechanisms of how VDR regulates the pathogenesis and progression of chronic liver disease, with the potential to develop vitamin D-related approaches for the treatment of disease.