Intracellular complement activation in Lupus Nephritis Podocytes

狼疮性肾炎足细胞的细胞内补体激活

基本信息

批准号：
10214745
负责人：
Abhigyan Satyam
金额：
$ 21.88万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-06 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214745
关键词：
American Antigen-Antibody Complex Antigens Biological CD4 Positive T Lymphocytes CRISPR/Cas technology Cathepsins Cathepsins B Cause of Death Cells Chronic Kidney Failure Cleaved cell Complement Complement Activation Complement Factor B Complement component C4 Cues Cytoplasm Deposition Development Epithelial Cells Exposure to Extrahepatic Family Fibroblasts Genetic Genetically Engineered Mouse Glomerulonephritis Graft Rejection Hemolytic-Uremic Syndrome Homeostasis Human Hypoxia Hypoxia Inducible Factor IGA Glomerulonephritis Immunoglobulin G Impairment In Vitro Inflammatory Injury Ischemia Kidney Diseases Kidney Failure Kidney Transplantation Lead Lupus Lupus Nephritis Maintenance Mediating Membrane Methods Mus Pathogenesis Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacology Process Production Proliferative Glomerulonephritis Protocols documentation Renal glomerular disease Research Role Specialized Epithelial Cell Surface System T-Lymphocyte Testing Tumor-Derived United States base cell injury cell type complement pathway complement system experimental study exposed human population genetically modified cells glomerular filtration glomerular function immune activation inhibitor/antagonist injured insight intestinal epithelium intestinal injury kidney epithelial cell knock-down lupus prone mice monocyte novel podocyte prevent renal damage response targeted delivery

项目摘要

Project Summary Deposition of immune complexes and activation of the complement system mediates glomerular injury and is involved in the inflammatory process in patients with lupus nephritis. Podocytes are highly specialized epithelial cells which are critical for the proper function of the glomerular filtration barrier and are injured in several proteinuric kidney diseases. Podocytes produce a number of complement factors and cathepsin proteases. Preliminary evidence suggests that podocytes exposed to IgG form patients with lupus nephritis produce increased amounts of complement which becomes activated intracellularly. We hypothesize that exposure of podocytes to IgG from patients with lupus nephritis or to hypoxia promotes the production and activation of complement intracellularly. We propose to identify complement components that are produced by podocytes after exposure to IgG from patients with lupus nephritis or hypoxia. Next, we will determine how cathepsin proteases activate complement intracellularly. For our studies we will use IgG from patients with lupus nephritis, a newly establish method to culture podocytes on surfaces coated with decellularized fibroblasts and podocytes from lupus-prone and cathepsin-deficient mice. CRISPR/Cas9 system will be utilized to knockdown C3 and cathepsins (B, L and S) in podocytes. The studies will produce a novel concept that intracellularly activated complement contributes to podocyte and glomerular damage independently of the deposited circulating complement. Our studies will point to the pursuit of avenues to limit increased production and activation of complement in podocytes in patients with lupus nephritis.

项目摘要免疫复合物的沉积和补体系统的激活介导肾小球损伤，IS 参与狼疮肾炎患者的炎症过程。足细胞高度专业上皮细胞对于肾小球滤过屏障的正常功能至关重要，并在几种蛋白尿肾脏疾病。足细胞产生许多补体因素和组织蛋白酶蛋白酶。初步证据表明，暴露于IgG的足细胞形成狼疮肾炎患者产生增加数量的补体，这些补体被细胞内激活。我们假设这一点暴露于狼疮性肾炎患者或缺氧患者的IgG上的足细胞会促进产生和细胞内补体的激活。我们建议识别产生的补体组件暴露于狼疮性肾炎或缺氧患者IgG后的足细胞。接下来，我们将确定如何组织蛋白酶蛋白酶细胞内激活补体。对于我们的研究，我们将使用患者的IgG 狼疮性肾炎，一种新建立的方法，用于涂有脱细胞的表面上培养足细胞来自狼疮和组织蛋白酶缺陷的小鼠的成纤维细胞和足细胞。 CRISPR/CAS9系统将是用于敲除C3和calter蛋白（B，L和S）的小c3。研究将产生一个新颖的概念细胞内激活的补体有助于足细胞和肾小球损伤沉积的循环补体。我们的研究将指出追求途径以限制增加狼疮性肾炎患者足细胞补体的产生和激活。