A Humanized Mouse Model of FSGS

 描述(申请人提供)：FSGS局灶节段性肾小球硬化(FSGS)人源化小鼠模型是一种以足细胞损伤、蛋白尿和进行性肾功能衰退为特征的严重肾小球疾病。这种疾病很可能在移植后复发，在30%的成年人中，甚至在儿童中更多。FSGS的原因是多方面的，包括足细胞基因突变、毒素以及循环因素，如可溶性尿激酶型纤溶酶原激活剂受体(SuPAR)。FSGS中suPAR升高的来源和特别有毒的suPAR形式正在调查中，但还没有动物模型可以模拟在人类FSGS中观察到的suPAR的影响。我们的初步数据显示，人源化小鼠-NOD-SCID IL2r空(NSG)免疫受损的小鼠移植了来自FSGS患者的外周血单个核细胞(PBMC)，在移植后大约三个月，出现了蛋白尿和小鼠suPAR水平升高的血浆和尿液。从小鼠实验中，我们进一步发现某些应激源，如内毒素，可以导致干样Gr-1low/Sca-1+骨髓细胞的扩张，这与血清和尿液suPAR的增加有关。我们假设来自FSGS患者的PBMC会触发干细胞样骨髓前体、suPAR和suPAR变体的产生，从而导致FSGS。在这项建议中，我们的目的是利用人源化小鼠技术建立和鉴定一种新的FSGS动物模型，并探讨FSGS发病的潜在机制。在目标1中，我们将全面开发和鉴定这种新型的FSGS人源化小鼠模型。目的2以干细胞样Gr-1low/Sca-1+细胞作为suPAR来源的生物学为重点，探讨FSGS发生的机制。FSGS人源化小鼠模型的建立将有助于我们更好地了解FSGS的发病机制，促进FSGS治疗方法的发现。

 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.