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：对复发性FSG（RFSG）的最新研究表明，CD40自动的潜在作用从FSGS患者血清分离的抗体（AUTOAB）。最有趣的是CD40 AutoAB和固体尿激酶受体（SUPAR）一起驱动开发啮齿动物中的肾病，虽然都不能正确地做到这一点。我们假设CD40 AutoAB在RFSG中起重要作用，或者是生物标志物或作为造成RFSG的伤害因素，该CD40 AutoAb和Supar 协同诱导FSG。阻止CD40或Supar-αVβ3整合素信号传导代表FSG的新型治疗概念。在这个研究计划中，我们提出一项高度创新和翻译的研究，具有三个独立但有凝聚力的旨在探索supar和CD40自动交互的机制肾脏损失。在AIM 1中，我们将评估CD40和CD40 AutoAb的含义 FSG。在AIM 2中，我们探讨了Supar和CD40 AutoAb是否在体内动物模型。在AIM 3中，我们将通过阻止SUPAR测试治疗概念诱导的足细胞β3整合素活性和/或通过干扰CD40相关的信号传导。总而该研究计划将有助于阐明FSG复发的发病机理，并还为FSG制定了新颖的针对性治疗策略。该研究结合在一起肾脏病，免疫学和足细胞生物学领域专家的独特专业知识，具有高临床影响的可交付成果，并立即转化为床边。