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.

摘要： 最近对复发性FSGS（rFSGS）的研究表明，CD 40自身抗体在FSGS中的潜在作用。 从FSGS患者血清中分离的抗体（autoAb）。最有趣的是，CD 40 autoAb和可溶性尿激酶受体（suPAR）共同推动了 在啮齿类动物中，没有一个人不能单独做得足够好。我们 假设CD 40自身抗体在rFSGS中作为生物标志物或 CD 40 autoAb和suPAR是rFSGS的损伤因子， 协同诱导FSGS。阻断CD 40或suPAR-αvβ3整合素信号传导可 代表FSGS的新治疗概念。因此，在这项研究计划中，我们 提出了一个高度创新和翻译的研究与三个独立但有凝聚力的 目的探讨suPAR和CD 40自身抗体相互作用导致CD 40表达异常的机制。 肾损伤在目标1中，我们将评估CD 40和CD 40自身抗体在 FSGS。在目的2中，我们探讨suPAR和CD 40 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CD 40相关信号传导。总的来说， 这项研究计划将有助于阐明FSGS复发的发病机制， 为FSGS开发新的靶向治疗策略。该研究结合了 肾脏学、免疫学和足细胞生物学领域专家的独特专业知识， 具有高度临床影响力的交付物，并立即转化为床边。