Cell-matrix interactions of renal tubular epithelial cells: implications of cortical actin structures and the tubular basement

• Applicant: Privatdozent Christoph B. Schell, Ph.D.
• Subject Area: Nephrology ; Pathology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438496892

Chronic kidney disease shows a persistent increase in incidence worldwide. Due to limited causal therapy options CKD often requires dialysis, which is related to high socio-economic cost burdens and also results in massively limited quality of life. Progressive organ dysfunction in the context of CKD is characterized by histomorphological features such as interstitial fibrosis and renal tubular atrophy. Hallmark features of renal tubular atrophy are phenotypical alterations of renal epithelial cells and massive thickening and multi-lamellation of the tubular basement membrane (TBM). Based on these observations and our preliminary work we hypothesize that alterations of TBM structure and composition might modulate the progress of tubular atrophy and moreover influences cell-matrix interactions ultimately leading to altered signaling and cellular crosstalk. Aside from specific matrix-receptors (e.g. integrin receptors) also cytoskeletal machineries are involved in balanced cell-matrix interactions. Although there is significant progress in the understanding of mechanisms modulating the process of renal fibrosis, the reciprocal interplay between altered TBMs and dysbalanced cell-matrix interactions are less understood. Therefore, we aim to address following questions in this project: 1) How is the renal tubular basement membrane composed? How is the composition of the TBM altered under pathological conditions? Are there specific ECM signatures present (in models of chronic kidney disease)? 2) What is the exact role of cortical actin networks in modulating cell-matrix interactions of renal tubular epithelial cells? Do these actin networks modulate ECM synthesis or processes such as mechano-transduction? 3) How do altered TBM structures influence renal epithelial biology (e.g. mechano-signaling)? Can these processes be modified by pharmacological interventions? The first question will be addressed employing innovative quantitative proteomics methods, ECM-enrichment protocols and in vivo mice models. Moreover, we´ve already established new conditional mice models allowing to analyze the role and contribution of cortical actin networks for renal tubular epithelial cells and the implications for cell-matrix interactions. Using a broad platform of primary cell systems, as well as CRISPR/Cas9 modified cell lines, biophysical approaches, a variety of ECM-protocols and co-culture assays we aim to elucidate how altered TBM structures influence epithelial phenotypes of renal tubular cells and how these effects translate into progressive renal tubular atrophy in the context of CKD.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Benedikt Sabass; Professor Dr. Oliver Schilling