A Humanized Mouse Model of FSGS

 描述（由申请人提供）：FSGS局灶节段性肾小球硬化（FSGS）的人源化小鼠模型是一种严重的肾小球疾病，其特征为足细胞损伤、蛋白尿和进行性肾功能下降。在30%的成年人中，这种疾病可能在移植后复发，在儿童中甚至更高。FSGS的原因有几个，包括足细胞基因突变，毒素以及循环因子，如可溶性尿激酶纤溶酶原激活物受体（suPAR）。目前正在研究FSGS中suPAR升高和特别有毒形式的suPAR的来源，但没有动物模型模拟在人FSGS中观察到的suPAR作用。我们的初步数据显示，人源化小鼠-移植有FSGS患者外周血单核细胞（PBMC）的NOD-scid IL 2 r null（NSG）免疫功能低下小鼠-在移植后约3个月出现蛋白尿和血浆和尿液中小鼠suPAR水平升高。从小鼠实验中，我们进一步发现某些应激源如LPS可导致干细胞样Gr-1 low/sca-1+骨髓细胞扩增，这与血清和尿液suPAR增加有关。我们假设FSGS患者的PBMC触发了干细胞样骨髓前体、suPAR和suPAR变体的扩增，这将导致FSGS。本研究拟利用人源化小鼠技术建立FSGS动物模型，探讨FSGS发病机制。在目标1中，我们将充分开发和表征这种新的FSGS人源化小鼠模型。目的2将研究FSGS发生的潜在机制，重点是干细胞样Gr-1 low/sca-1+骨髓细胞作为suPAR来源的生物学。建立人源化小鼠FSGS模型将有助于我们更好地了解FSGS的发病机制，并有助于发现这种疾病的治疗方法。

 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.