A Humanized Mouse Model of FSGS



 DESCRIPTION (provided by applicant): A humanized mouse model of FSGS Focal segmental glomerulosclerosis (FSGS) is a severe glomerular disease that is characterized by podocyte injury, proteinuria, and progressive renal decline. The disease is likely to recur after transplantation in 30% of adults and even in higher number in children. The causes of FSGS are several and include podocyte gene mutations, toxins as well as circulating factors such as the soluble urokinase plasminogen activator receptor (suPAR). The source of elevated suPAR and of particularly toxic forms of suPAR in FSGS are under investigation but there is no animal model that mimics the effects of suPAR as observed in human FSGS. Our preliminary data showed that humanized mice - NOD-scid IL2r¿null (NSG) immunocompromised mice engrafted with peripheral blood mononuclear cells (PBMCs) from patients with FSGS - developed proteinuria and elevated mouse suPAR levels in both plasma and urine, approximately three months after engraftment. From mouse experiments, we further discovered that certain stressors such as LPS can lead to the expansion of stem-like Gr-1low/sca-1+ bone marrow cells which is associated with increased serum and urine suPAR. We hypothesize that PBMCs from FSGS patients trigger expansion of stem-like bone marrow precursors, suPAR and suPAR variant production that will cause FSGS. In this proposal, we aim to develop and characterize a novel FSGS animal model using the technology of humanized mice and to explore the underlying mechanisms of FSGS pathogenesis. In Aim 1, we will fully develop and characterize this novel humanized mouse model of FSGS. Aim 2 will serve to investigate the mechanisms underlying the development of FSGS with focus on the biology of stem-like Gr-1low/sca-1+ bone marrow cells as source of suPAR. Developing the humanized mouse model of FSGS will allow us to better understand the pathogenesis of FSGS and facilitate the discovery of therapeutics for this disease.