Project Details
Projekt
Modulation of the podocyte actin network
Subject Area
Nephrology
Term
from 2013 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 241702976
The glomerular filtration barrier is composed of fenestrated endothelium, the glomerular basement membrane and highly specialized epithelial cells, namely podocytes. Dysfunction in any of these components presents the basis for glomerular diseases, which represent the main cause for chronic kidney disease and end stage renal kidney disease. Podocytes have a highly complex cellular morphology with numerous extensions and rely on a specialized cytoskeleton in order to maintain their morphology. Most forms of podocyte injury are characterized by a restructuring of the cytoskeleton and a retraction of podocyte foot processes. We propose that a comprehensive understanding of the podocyte cytoskeleton will allow the development of novel diagnostic as well as therapeutic interventions. In the previous funding period we could demonstrate the fundamental role of the N-WASP/Arp2/3 actin nucleation machinery to maintain morphology and function of podocytes. Based on these results we are aiming to answer the following questions: 1) How does the cortical and branched actin network interact with other cytoskeletal machineries (e.g. actomyosin)? Can these interactions be modulated by pharmacological interventions? 2) How does the podocyte actin cytoskeleton modulate the interaction with the glomerular basement membrane? Is this interplay involved in the prevention of podocyte detachment? 3) Which role do podocyte specific RhoGTPase modulators play for the integrity of the glomerular filtration barrier? The first two questions will be answered by the use of newly established in vitro models including 3D-culture systems, biophysical measurements and proteomics. The actin cytoskeleton is regulated via numerous signaling pathways including RhoGTPases and their upstream activators/inhibitors (GAPs and GEFs). We could already identify one podocyte specific GAP based on highly pure single cell isolation procedures and subsequent application of multi-plattform omics-technologies. We´ve generated a novel conditional knockout model to study the in vivo relevance of this podocyte specific GAP under physiological as well as pathological conditions. Moreover, we will perform further functional in vitro studies and proteomics to understand the precise role of this GAP for podocytes.
DFG Programme
Research Grants
