CD40 autoantibody and FSGS recurrence

CD40自身抗体与FSGS复发

• 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
• 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

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.

摘要： 最近对复发性FSGS(RFSGS)的研究表明CD40自身- 从FSGS患者血清中分离出的抗体(AutoAb)。最有趣的是，CD40 自身抗体和可溶性尿激酶受体(SuPAR)共同推动血管内皮细胞瘤的发生 啮齿类动物的肾病，而这两个人都不能单独做到这一点。我们 假设CD40自身抗体在rFSGS中作为生物标志物或 作为导致rFSGS的损伤因素，CD40自动抗体和suPAR 协同诱导FSGS。阻断CD40或suPAR-αvβ3整合素信号转导可能 代表了FSGS的新治疗概念。因此，在这个研究项目中，我们 提出一项具有高度创新性和翻译性的研究，包括三个独立但有凝聚力的研究 旨在探讨suPAR和CD40自身抗体相互作用的机制。 肾脏受损。在目标1中，我们将评估CD40和CD40自身抗体在慢性粒细胞白血病中的意义。 FSGS。在目标2中，我们探讨了suPAR和CD40自身抗体是否以及如何诱导FSGS。 活体动物模型。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CD3整合素活性和/或干扰β相关信号转导。总而言之， 这项研究计划将有助于揭开FSGS复发和 开发针对FSGS的新的靶向治疗策略。该研究结合了 肾脏病、免疫学和足细胞生物学领域专家的独特专业知识， 具有高临床影响力的可交付成果，并可立即转移到床边。