Delineating cell type, mechanism, consequences and targeting of TGF-β2 expression in biliary liver disease

• Applicant: Anne Dropmann, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459725563

Chronic liver diseases (CLD) are a major health concern since fibrotic deteriorations progress to cirrhosis and liver cancer, the second deadliest cancer type worldwide. Primary sclerosing cholangitis (PSC) belongs to rare chronic autoimmune liver diseases that lead to the destruction of the biliary system. Starting with liver damage from persistent cholestasis, chronic portal inflammation and fibrosis in proximity of intrahepatic and extrahepatic bile ducts lead to cirrhotic rearrangements that compromise liver function. These PSC patients exhibit a 10–15% lifetime risk to develop cholangiocarcinoma (CCA).As liver transplantation is the only curative treatment opportunity so far, new therapeutic options are needed for the management of PSC. We recently identified TGF-β2 as specific biomarker and new potential treatment target for PSC, and possibly also for CCA. In this project, we aim to delineate in much detail the impact of TGF-β2 on CLD progression in PSC to justify a future clinical trial in patients. Specifically, we will analyse TGF-β2 expression regulation and TGF-β2 mediated signal transduction in the liver in a spatial and cell type specific manner during cholestatic disease progression in the ABCB4KO mouse model and in human PSC specimen. Furthermore, we will perform acute and chronic treatment of wildtype and ABCB4KO mice with TGF-β2 injection, at early intermediate and late disease stages, and depict the impact of TGF-β2 on parenchymal and non-parenchymal cell types, on liver (patho)morphology, and in particular fibrogenesis and inflammation. Thus, we will get insights on the role of TGF-β2 in the pathogenesis of biliary liver damage and disease progression in highest resolution, including a discrimination between TGF-β2 and TGF-β1 effects. Finally, we will target TGF-β2 expression using an established antisense oligonucleotide in CCA patient-derived organoids, as a preliminary test for a potential beneficial impact on tumor progression by estimating tumor growth, proliferative activity, stroma composition and chemoresistance. The project results will provide insight in the basics of TGF-β2 biology, specifically in liver cells and in the context of cholestatic liver disease and PSC. Data will also facilitate decision making in setting up a TGF-β2 directed clinical trial in PSC patients. Finally, we hope to see evidence that targeting TGF-β2 is a promising new treatment approach for patients with CCA.

• DFG Programme: Research Grants
• International Connection: Poland, United Kingdom
• Cooperation Partners: Luke Boulter; Professorin Dr. Malgorzata Milkiewicz; Professor Piotr Milkiewicz, Ph.D.; Palak Trivedi