Project Summary/Abstract Glomerular injury leads to proteinuric kidney diseases that often progress to renal failure. Despite advances in our understanding of the pathogenesis of glomerular disease, current treatment relies heavily on immunosuppressive or anti-hypertensive drugs and specific treatments are still lacking. Regardless of the underlying cause, one early and unifying event in glomerular injury is a morphological change in podocytes called foot process (FP) effacement. Activation of αvβ3 integrin on podocytes is linked to early pathological processes leading to FP effacement and the subsequent induction of proteinuria in several glomerular diseases, including FSGS and DN. Conversely, blocking of αvβ3 activation significantly reduces proteinuria and subsequent disease progression in animal models of FSGS and DN. However, there is currently no clinically successful approach designed to target αvβ3 integrin. We recently discovered a novel role for inducible co-stimulator ligand (ICOSL) in the protection against early glomerular injury (Koh et al., JCI, 2019). Glomerular ICOSL expression increases in early stages of human FSGS and DN, followed by a drastic decline at later stages. ICOSL deficient animals are more susceptible to kidney injury and severe proteinuria, and can be rescued by recombinant ICOSL injection. ICOSL’s RGD motif is critically important for binding to activated αvβ3 as well as its protective function. Despite this important discovery that ICOSL contributes to kidney protection, more detailed mechanistic studies are necessary to fully understand the renoprotective behavior of ICOSL as a regulator of αvβ3 integrin and to develop targeted therapies. Based on our published and preliminary data, we hypothesize that elevated ICOSL expression is a mechanism launched by podocytes as an endogenous defensive response to limit progressive kidney injury by counterbalancing the harmfully excessive activation of αvβ3 integrin. To test this hypothesis, we will precisely define the essential temporal and spatial regulation of ICOSL expression necessary to deploy its protective action (Aim 1), determine how ICOSL achieves renoprotection (Aim 2), and explore its therapeutic potential (Aim 3). Our studies will be essential steps in moving toward successful development of novel specific therapeutics for αvβ3 integrin-mediated glomerular diseases.