CD40 autoantibody and FSGS recurrence

CD40自身抗体与FSGS复发

• 批准号: 9333947
• 负责人: Jochen Reiser
• 金额: $ 56.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/9333947
• 关键词: Adult; Affinity; Animal Model; Antibodies; Autoantibodies; Binding; Biological Assay; Biological Markers; Biology; Biopsy; 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; Integrin alphaVbeta3; Integrin beta3; 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; high throughput screening; in vivo; in vivo Model; innovation; mouse model; new therapeutic target; novel; novel therapeutics; podocyte; programs; protein structure; synergism; therapeutic evaluation; therapy resistant; transcriptome sequencing; translational study

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，而其中任何一种都无法单独完成这一任务。我们 假设 CD40 autoAb 作为生物标志物或在 rFSGS 中发挥重要作用 作为导致 rFSGS 的损伤因素，CD40 autoAb 和 suPAR 协同诱导 FSGS。阻断 CD40 或 suPAR-αvβ3 整合素信号传导可以 代表了 FSGS 的新颖治疗概念。因此，在这个研究计划中，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 肾损害。在目标 1 中，我们将评估 CD40 和 CD40 autoAb 在 FSGS。在目标 2 中，我们探讨了 suPAR 和 CD40 autoAb 是否以及如何诱导 FSGS 体内动物模型。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。总而言之， 该研究计划将有助于揭示 FSGS 复发的发病机制和 还为 FSGS 开发新的靶向治疗策略。该研究结合了 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。