A Humanized Mouse Model of FSGS

FSGS 人源化小鼠模型

• 批准号: 9070608
• 负责人: Jochen Reiser
• 金额: $ 20.93万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070608
• 关键词: Adult; Albumins; Animal Model; Applications Grants; Biochemical; Biology; Bone Marrow; Bone Marrow Cells; CD34 gene; Cells; Child; Chronic Disease; Clinical; Creatinine; Data; Development; Dialysis procedure; Disease; Electron Microscopy; Engraftment; Etiology; Exhibits; Focal Segmental Glomerulosclerosis; Foot Process; Gene Mutation; Goals; Health; Histologic; Human; Immunocompromised Host; In Vitro; Injury; Investigation; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Lead; Lesion; Modeling; Mus; Nephrotic Syndrome; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Play; Population; Production; Proteinuria; Renal glomerular disease; Rodent Model; Serum; Source; Stem cells; Technology; Testing; Therapeutic; Toxin; Translating; Transplantation; Urine; Urokinase Plasminogen Activator Receptor; Variant; Virus; allograft rejection; cytokine; healthy volunteer; humanized mouse; improved; in vivo; mouse model; novel; podocyte; precursor cell; research study; response; stem; stressor; tool; urinary

 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.

 描述（申请人提供）：FSGS 人源化小鼠模型 局灶节段性肾小球硬化症（FSGS）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衰退。 30% 的成人移植后该疾病可能会复发，儿童中的复发率更高。 FSGS 的原因有多种，包括足细胞基因突变、毒素以及可溶性尿激酶纤溶酶原激活剂受体 (suPAR) 等循环因子。 FSGS 中升高的 suPAR 和特别有毒形式的 suPAR 的来源正在研究中，但没有动物模型可以模拟人类 FSGS 中观察到的 suPAR 的作用。我们的初步数据显示，人源化小鼠——移植了来自 FSGS 患者的外周血单核细胞 (PBMC) 的 NOD-scid IL2r¿null (NSG) 免疫功能低下小鼠——在植入大约三个月后出现蛋白尿，并且血浆和尿液中的小鼠 suPAR 水平升高。通过小鼠实验，我们进一步发现某些应激源（如 LPS）可导致干细胞样 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细胞的扩增、suPAR 和 suPAR 变异体的产生，从而导致 FSGS。在本提案中，我们的目标是利用人源化小鼠技术开发和表征新型 FSGS 动物模型，并探索 FSGS 发病机制的潜在机制。在目标 1 中，我们将全面开发并表征这种新型 FSGS 人源化小鼠模型。目标 2 将研究 FSGS 发展的潜在机制，重点关注作为 suPAR 来源的干细胞样 Gr-1low/sca-1+ 骨髓细胞的生物学。开发 FSGS 人源化小鼠模型将使我们能够更好地了解 FSGS 的发病机制，并有助于发现该疾病的治疗方法。