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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：
10343847
负责人：
Abhigyan Satyam
金额：
$ 26.25万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343847
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 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 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，狼疮性肾炎患者的生活质量如何？足细胞高度特化上皮细胞对肾小球滤过屏障的正常功能至关重要，几种蛋白尿肾病。足细胞产生许多补体因子和组织蛋白酶蛋白酶初步证据表明，足细胞暴露于IgG形成狼疮肾炎患者产生大量的补体，其在细胞内被激活。我们假设将足细胞暴露于狼疮肾炎患者的IgG或缺氧促进产生和细胞内补体的激活。我们建议确定产生的补体成分，狼疮性肾炎或缺氧患者的IgG暴露后，足细胞。接下来，我们将确定如何组织蛋白酶在细胞内激活补体。对于我们的研究，我们将使用来自患有以下疾病的患者的IgG：狼疮性肾炎，一种新建立的在脱细胞表面上培养足细胞的方法成纤维细胞和足细胞从狼疮倾向和组织蛋白酶缺陷的小鼠。CRISPR/Cas9系统用于敲低足细胞中的C3和组织蛋白酶（B、L和S）。这些研究将产生一个新的概念，细胞内激活的补体导致足细胞和肾小球损伤，沉积的循环补体。我们的研究将指出寻求途径，以限制增加狼疮性肾炎患者足细胞中补体的产生和激活。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activation of classical and alternative complement pathways in the pathogenesis of lung injury in COVID-19.

DOI：
10.1016/j.clim.2021.108716
发表时间：
2021-05
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
0
作者：
Satyam A;Tsokos MG;Brook OR;Hecht JL;Moulton VR;Tsokos GC
通讯作者：
Tsokos GC

Intertwined pathways of complement activation command the pathogenesis of lupus nephritis.

DOI：
10.1016/j.trsl.2022.03.005
发表时间：
2022-07
期刊：
TRANSLATIONAL RESEARCH
影响因子：
7.8
作者：
Satyam, A. B. H. I. G. Y. A. N.;Hisada, R. Y. O.;Bhargava, R. H. E. A.;Tsokos, Maria g.;Tsokos, George c.
通讯作者：
Tsokos, George c.