Wednesday, April 2, 2025
4/2/2025
Determination of Molecular Mechanism of Stellate Cell-Mediated Fibrosis - Liver fibrosis is the consequence of chronic liver diseases, such as hepatitis B and C infection and alcoholic and non-alcoholic steatohepatitis. Cirrhosis is the end stage of liver fibrosis and is associated with life-threatening complications, including liver failure, portal hypertension, and hepatocellular carcinoma. The progression of liver fibrosis leads to the formation of bridging fibrosis, resulting in the development of cirrhosis. The molecular mechanism of the progression of liver fibrosis is not fully understood. In this project, we focus on the mechanism of HSC invasion and ECM remodeling, which is required for extending fibrosis bands to form bridging fibrosis. Our preliminary data show that Wilms tumor 1 (WT1) is one of the most enriched transcription factors in HSCs that have invaded/migrated. WT1 inhibition reduced HSC invasion, extracellular matrix (ECM) production, and the development of liver fibrosis in mice. We also found that the WT1 promoter region contains hypoxia-inducing factor (HIF)-binding elements and WT1 is one of the most enriched transcription factors in HSCs under hypoxic challenge. Based on these preliminary data, the proposed study will investigate the mechanism of WT1-mediated HSC invasion, ECM remodeling, and the development of liver fibrosis. We hypothesize that the fibrosis-mediated hypoxic environment upregulates WT1 expression in HSCs. This promotes HSC invasion, ECM production and remodeling, promoting the development of liver fibrosis. Aim 1 will investigate the mechanism of WT1-mediated HSC invasion and pro-fibrogenic role of WT1 expression in HSCs in liver fibrosis using HSC-specific Wt1 knockout mice. Analysis of bulk and single-cell RNA-sequencing and digital spatial profiling of whole transcriptomic profiles will identify the role of WT1 in the induction of HSC populations associated with ECM production and HSC migration and invasion. Because the WT1 promoter region contains multiple HIF-binding elements, Aim 2 will investigate the mechanisms of hypoxia and HIF-1-mediated WT1 induction in HSCs. Aim 3 will examine the role of the WT1 downstream effector Cathepsin K in HSC invasion, ECM digestion and remodeling. We will also test the hypothesis that Cathepsin K can be a therapeutic target for ongoing and progressive liver fibrosis. We will also examine the expression of WT1 and its downstream effectors in human liver specimens. Our results will identify a new mechanism for HSC biology, including HSC invasion, WT1 induction, ECM remodeling, and the development of liver fibrosis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).