报告题目：TGF-β signaling regulation in liver disease and liver regeneration: Role of ECM1 and signaling crosstalk in liver progenitor cells
报告人：Steven Dooley 教授
主持人：冯新华 教授
时 间：2025年3月26日（周三）下午4点
地 点：纳米楼457报告厅
报告人简介：
Steven Dooley is University Professor and Head of Section of Molecular Hepatology & Alcohol Associated Diseases in the Department of Medicine II at the Medical Faculty Mannheim, at Heidelberg University. Prof. Dooley graduated in Biology at the University at Kaiserslautern and did his PhD studies at the Institute of Human Genetics, University of Saarland in Homburg. His Postdoc research on Molecular Cancer Research took place at the Institute of Human Genetics at the same University. Later in 1998, he became Group Leader and Assistant Professor in the Department of Clinical Chemistry and Pathobiochemistry at the University Hospital RWTH Aachen. In 2004, he was appointed as a full Professor to Heidelberg University.
Prof. Dooley received the Gábor-Szász-Award of the Deutsche Vereinte Gesellschaft für Klinische Chemie und Laboratoriums-Medizin for outstanding scientific merits. He has over 200 publications and his work is supported by different grants from, among others DFG, BMBF and EU. His research is dedicated to cellular processes that occur in the liver in response to damage, e.g. from alcohol abuse or malnutrition, specifically in the role of TGF-β family members, their signaling pathway regulators and target genes. His group is using molecular biology, cell biology, imaging and systems biology in cells, animal models and samples from human patients with liver disease to understand disease mechanisms and find new targets to be used for diagnosis or therapy.
Abstract：
The matrisomal protein Extracellular Matrix Protein 1 (ECM1) serves as a gatekeeper in the liver by maintaining tissue homeostasis. Its depletion causes lethal hepatic fibrosis resulting from excessively high levels of active TGF-β. In patients suffering from chronic liver disease and HCC, the expression of ECM1 is decreased. Severe liver fibrosis in Ecm1-KO mice, mouse models for liver disease and in patients is accompanied by upregulation of mediators of latent TGF-β activation including TSPs, ADAMTS proteases and MMPs. The ectopic supply abrogated TSP-1, ADAMTS1, MMP-2/9-mediated TGF-β activation in cultured HSCs. Interaction studies pinpointed ECM1's inhibitory effect to physical interactions with the respective LTGFB. We identified peptide sequences TSP1 (KRFK) and ADAMTS (KTFR) that either could be targeted by or phenocopied ECM1 with respective results in liver fibrosis mouse models. These findings underscore the hepatoprotective effect of ECM1, suggesting strategies for preventing ECM1 from decreasing or restoring its function in the liver to inform novel and safer anti-fibrotic therapies.
