Role of the podocyte adhesome in the development of FSGS

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Regardless of the underlying etiology, podocytes exhibit a uniform alteration in cellular morphology in pathological conditions of focal segmental glomerulosclerosis (FSGS). While one of the earliest detectable changes is characterized as a prominent retraction and simplification of the podocyte foot process network, increasing detachment of podocytes from the glomerular basement membrane is observed at later stages and finally results in progressive podocyte loss. These morphological observations and the identification of disease-causing mutations in adhesion genes such as ITGA3 and CD151 in the context of hereditary podocytopathies have demonstrated the outstanding relevance of the podocyte adhesion machinery. Fine-tuned adhesion of podocytes is controlled by the integrin adhesome, a multi-protein complex that is directly interconnected with the cytoskeleton. Despite significant progress, a comprehensive understanding of the adhesion-cytoskeletal nexus and its dedicated role in the pathogenesis of FSGS is lacking. The overarching goal of this proposal is to characterize dynamic alterations of the podocyte adhesome and to investigate their impact in the context of FSGS. Specifically, we will address 3 aims: (Aim 1) by combining high-resolution proteomics and multidimensional imaging approaches we will describe alterations in adhesome signatures in different stages and models of FSGS. (Aim 2) By employing novel inducible mouse models we will investigate how the central IPP complex of the adhesome controls mechano-physical adaptation of podocytes and thereby prevents podocyte detachment. (Aim 3) Finally, we will use a complementary approach based on in vitro and in vivo models to investigate the role of podocyte-specific GTPase modulators and their influence on the podocyte adhesome. In summary, our project will not only contribute to a comprehensive understanding of pathogenetic changes in the podocyte adhesion machinery in the context of FSGS but will also provide the framework for the generation of grading systems of podocyte damage which could be eventually used for stratification.