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 IL2rnull (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.

Public Health Relevance

The goal of this grant proposal is to develop a novel humanized mouse model to study the pathogenesis of focal segmental glomerulosclerosis (FSGS). If our hypothesis is correct, we can induce bone marrow precursor cells in NSG mice after transfer of peripheral blood mononuclear cells (PBMCs) from patients with FSGS. Production of bone-marrow derived soluble urokinase plasminogen activator receptor (suPAR) will cause development of FSGS. This model will be a widely usable tool, which will allow for the studies of circulating factors in the pathogenesis of proteinuric kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK106051-02
Application #
9070608
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Moxey-Mims, Marva M
Project Start
2015-06-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Peev, Vasil; Hahm, Eunsil; Reiser, Jochen (2017) Unwinding focal segmental glomerulosclerosis. F1000Res 6:466
Hayek, Salim S; Koh, Kwi Hye; Grams, Morgan E et al. (2017) A tripartite complex of suPAR, APOL1 risk variants and ?v?3 integrin on podocytes mediates chronic kidney disease. Nat Med 23:945-953
Hahm, Eunsil; Peev, Vasil; Reiser, Jochen (2017) Extrarenal determinants of kidney filter function. Cell Tissue Res 369:211-216
Hahm, Eunsil; Wei, Changli; Fernandez, Isabel et al. (2017) Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 23:100-106