Project Details
Projekt
Understanding the role of macrophage-fibroblast networks in extracellular matrix turnover and recycling.
Applicant
Professor Dr. Stefan Uderhardt
Subject Area
Immunology
Anatomy and Physiology
Cell Biology
Anatomy and Physiology
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 533863915
This research proposal aims to unravel the intricate mechanisms of extracellular matrix (ECM) homeostasis, focusing on the cooperative roles of macrophages and fibroblasts in hyaluronic acid (HA) metabolism. The project seeks to elucidate a novel concept of transcellular metabolic synergy in ECM turnover, with potential implications for various tissues and organs. The study will investigate the hypothesis that lysosomal sugar shuttling via specific channels constitutes a functional bottleneck for synergistic HA turnover between macrophages and fibroblasts, and that deficient sugar efflux leads to inflammatory responses causing ECM pathology. This study will be conducted through three main aims: 1) Dissecting endosomal shuttling of HA-derived sugar in macrophages in vitro, 2) Resolving transcellular hyaluronan building block trafficking in vitro, and 3) Dissecting HA turnover in synovial tissues in vivo. Experiments will employ cutting-edge techniques such as high-resolution confocal microscopy, live-cell imaging, metabolomics, RNA sequencing, and innovative 3D tissue imaging approaches. The project will utilize various in vitro systems, including mono- and co-cultures of bone marrow-derived macrophages and fibroblasts, as well as sophisticated in vivo models using genetically modified mice. Key experiments include characterizing HA uptake and processing mechanisms, investigating the role of specific sugar transporters (e.g., SLC17A5) in HA metabolism, and examining the consequences of impaired HA degradation on lysosomal function and cellular stress responses. The research will also explore the potential cooperative synergism between macrophages and fibroblasts in HA turnover using advanced co-culture systems and 3D micromass cultures. In vivo studies will focus on mapping synovial tissue architecture and cellular interactions at subcellular resolution, providing unprecedented insights into the complex interplay between different cell types in ECM homeostasis. This project is significant as it addresses fundamental questions in tissue biology and ECM regulation, with potential implications for understanding and treating degenerative joint diseases and other ECM-related pathologies. By elucidating the molecular mechanisms underlying HA metabolism and the functional cooperation between macrophages and fibroblasts, this research may pave the way for novel therapeutic strategies targeting ECM dysregulation in various pathological conditions. The innovative approaches and techniques employed in this study promise to provide a comprehensive understanding of ECM homeostasis, bridging the gap between cellular mechanisms and tissue-level processes in health and disease.
DFG Programme
Research Units
