CD40 autoantibody and FSGS recurrence

CD40自身抗体与FSGS复发

基本信息

批准号：
9912137
负责人：
Jochen Reiser
金额：
$ 54.27万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912137
关键词：
Adult Affinity Animal Model Antibodies Autoantibodies Binding Biological Assay Biological Markers Biology CD40 Antigens Child Chronic Clinical Cytoskeleton Development Dialysis procedure Disease Evaluation Focal Segmental Glomerulosclerosis Functional disorder Genetic Transcription Histology Human Hybridomas ITGB3 gene Immunology In Vitro Individual Injury Injury to Kidney Integrin alphaVbeta3 JAK3 gene Kidney Kidney Diseases Kidney Failure Kidney Transplantation Knockout Mice Lesion Libraries Measurement Measures Mediating Messenger RNA Modeling Nephrology Organ Pathogenesis Pathogenicity Patients Phenotype Play Principal Investigator Process Production Protein Glycosylation Proteins Proteinuria Recurrence Research Risk Rodent Role Signal Pathway Signal Transduction Suggestion Sum TNFRSF5 gene Therapeutic Therapeutic Agents Transgenic Mice Translations Urokinase Plasminogen Activator Receptor base biomarker identification cell motility clinically relevant cohesion exposed human population high throughput screening in vivo in vivo Model innovation kidney biopsy mouse model new therapeutic target novel novel therapeutics podocyte programs protein structure renal damage synergism therapeutic evaluation therapy resistant transcriptome sequencing translational study

项目摘要

ABSTRACT: Recent studies in recurrent FSGS (rFSGS) suggest a potential role for CD40 auto- antibody (autoAb) isolated from the sera of FSGS patients. Most interestingly, CD40 autoAb and soluble urokinase receptor (suPAR) together drive the development of nephropathy in rodents, while neither one could not do it alone sufficiently. We hypothesize that CD40 autoAb plays an important role in rFSGS either as a biomarker or as an injury factor contributing to rFSGS, and that CD40 autoAb and suPAR synergistically induce FSGS. Blocking CD40 or suPAR-αvβ3 integrin signaling could represent novel therapeutic concepts for FSGS. Thus in this research program, we propose a highly innovative and translational study with three independent but cohesive Aims to explore the mechanisms of suPAR and CD40 autoAb interaction that cause renal damages. In Aim 1, we will assess the implication of CD40 and CD40 autoAb in FSGS. In Aim 2, we explore whether and how suPAR and CD40 autoAb induce FSGS in animal models in vivo. In Aim 3, we will test the therapeutic concepts by blocking suPAR induced podocyte β3 integrin activity and/or by interfering CD40 related signaling. In sum, this research program will help unravel the pathogenesis of FSGS recurrence and develop novel targeted therapeutic strategies for FSGS as well. The study combines unique expertise of domain experts in nephrology, immunology and podocyte biology, with deliverables of high clinical impact and immediate translation to the bedside.

抽象的：最近对复发性 FSGS (rFSGS) 的研究表明 CD40 自动调节的潜在作用从 FSGS 患者血清中分离出的抗体（autoAb）最有趣的是 CD40。 autoAb 和可溶性尿激酶受体 (suPAR) 共同驱动啮齿类动物的肾病，而我们单独一人无法做到这一点。研究表明 CD40 autoAb 在 rFSGS 中作为生物标志物或作为导致 rFSGS 的损伤因素，CD40 autoAb 和 suPAR 阻断 CD40 或 suPAR-αvβ3 整合素信号传导可以协同诱导 FSGS。代表了 FSGS 的新颖治疗概念，因此在这个研究项目中，我们提出一项高度创新和转化的研究，其中包括三个独立但有凝聚力的研究旨在探讨suPAR与CD40自身抗体相互作用导致的机制在目标 1 中，我们将评估 CD40 和 CD40 autoAb 在肾损伤中的影响。在目标 2 中，我们探讨了 suPAR 和 CD40 autoAb 是否以及如何诱导 FSGS。在目标 3 中，我们将通过阻断 suPAR 来测试治疗概念。诱导足细胞 β3 整合素活性和/或通过干扰 CD40 相关信号传导。该研究计划将有助于揭示 FSGS 复发的发病机制和该研究还结合了 FSGS 开发新的靶向治疗策略。肾病学、免疫学和足细胞生物学领域专家的独特专业知识，具有高度临床影响并立即转化为床边的交付成果。