Targeting force regulation to treat kidney disease (360G-Wellcome-202860_Z_16_Z)

Kidney disease affects 10% of the global population and glomerular disease is the leading cause of kidney failure. Glomerular capillaries filter the blood across a specialised filtration barrier comprised of endothelial cells, podocytes and an intervening glomerular basement membrane (GBM). Podocyte adhesion to the GBM is essential for barrier integrity and ultimately for kidney survival. Using proteomics and ultrastructural analyses we have expanded the molecular landscape of cell-matrix adhesion in the glomerulus and have identified GBM defects and podocyte protrusions into the GBM as novel morphological features of early disease. However a mechanistic understanding about altered GBM and secondary effects on podocyte adhesion remain unclear. I now hypothesise that that cell-matrix interactions in the glomerular capillary wall are critical to counterbalance intracapillary forces and if disrupted there is a cascade that leads to glomerulosclerosis. I will define molecular mechanisms of glomerular force regulation in cell and mouse models of glomerular disease. This proposal will have impact by defining mechanisms of capillary wall homeostasis and by identifying therapeutic targets to treat chronic kidney disease.