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（由适用提供）：FSGS局灶性分段肾小球硬化症（FSGS）的人源化小鼠模型是一种严重的肾小球疾病，其特征在于足细胞损伤，蛋白尿和进行性肾脏下降。在30％的成年人中，甚至在儿童中，该疾病可能会复发。 FSG的原因有几种，包括足细胞基因突变，毒素以及循环因子，例如可溶性尿激酶纤溶酶原激活剂受体（SUPAR）。正在研究FSG中升高的supar和特别有毒的supar形式的来源，但是没有动物模型模仿人类FSG中观察到的supar的作用。我们的初步数据表明，人源化小鼠-NOD -SCIDIL2R¿NULL（NSG）免疫功能低下的小鼠，患有外周血单核细胞（PBMC）的FSGS患者 - 发育于蛋白尿中的FSGS患者（PBMC），在血浆和尿液中，插入了大约三个月的蛋白尿和小鼠SUPAR水平。从小鼠实验中，我们进一步发现，某些应激源（例如LPS）可以导致茎状的GR-1LOW/SCA-1+骨髓细胞的扩展，这与血清和尿液supar的增加有关。我们假设来自FSGS患者的PBMC会触发会导致FSGS的茎状骨髓前体，Supar和Supar变体产生的扩展。在此提案中，我们旨在使用人源化小鼠的技术开发和表征一种新型的FSGS动物模型，并探索FSGS发病机理的基本机制。在AIM 1中，我们将充分发展并表征这种新型FSG的人源性小鼠模型。 AIM 2将用于研究FSG发展的基础机制，重点是茎样GR-1LOW/SCA-1+骨髓细胞作为Supar的来源。开发人源化的FSG小鼠模型将使我们能够更好地了解FSG的发病机理，并促进对该疾病的治疗发现。