EXPERIMENTAL HUMAN IGA MEDIATED NEPHROPATHY

实验性人类 IGA 介导的肾病

• 批准号: 2150078
• 负责人: ABDALLA RIFAI
• 金额: $ 23.73万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2150078
• 关键词: T lymphocyte; cell adhesion molecules; chimeric proteins; complement; cytokine; disease /disorder model; extracellular matrix; glomerulonephritis; immune complex; immunoglobulin A; laboratory mouse; lipoxygenase; macrophage; metalloendopeptidases; model design /development; molecular cloning; neutrophil; nucleic acid sequence; prostaglandin endoperoxide synthase; tissue /cell culture; tissue inhibitor of metalloproteinases

The pathogenesis of IgA nephropathy, the most common form of glomerulonephritis in the world, is still largely unknown. The relationship between glomerular IgA deposits and development of renal lesions that precipitate in renal failure, have not been elucidated. On the basis of experimental and clinical observations we hypothesize that in glomerular IgA deposits the structure of IgA and the complexed antigen (IgA-IC) activate glomerular responses that trigger leukocytic infiltration. Proinflammatory cytokines from infiltrating cells induce or augment the generation of growth factors. The interplay of synergistic and antagonistic elements within this network alter the composition and production of the extracellular matrix that consummates in glomerular sclerosis, interstitial fibrosis, and renal failure. A comprehensive human IgA-mediated nephropathy experimental model will be developed in a T and B lymphocytes-deficient, Recombination Activation Gene-disrupted (knockout), mice. This model will provide a framework for elucidating in vivo the cellular and molecular mechanisms that are associated with glomerular human IgA immune deposits. To develop the model and evaluate the hypothesis, the following specific aims will be addressed: 1. We will construct human IgA1 and IgA2 as antigen-specific chimeric antibodies for formation of human IgA immune complexes. 2. We will elucidate the primary mechanisms that lead to human IgA-IC glomerular localization. 3. We will identify the mediators of glomerular responses to human IgA-IC by examining:complement deposition, procoagulant activation, phenotypic and genotypic expression of Selectins, and chemokines. 4. We will determine the nephritogenic profile of proinflammatory cytokines and growth factors in renal tissues with IgA immune deposits. 5. We will characterize in a chronic model of human IgA nephropathy the differential expression of extracellular matrix genes involved in the progressive stages of fibrosis associated with renal failure. These studies will provide an insight into cellular and molecular mechanisms underlying the pathogenesis of IgA nephropathy that can be targeted for development of therapy and prevention of progression to renal failure.

伊加肾病的发病机制，最常见的形式， 肾小球肾炎在世界上，仍然在很大程度上未知。的关系 肾小球伊加沉积和肾脏病变的发展之间的关系， 肾衰竭中的沉淀物，尚未阐明。 根据实验和临床观察，我们假设， 在肾小球伊加沉积伊加的结构和复合抗原 （IgA-IC）激活肾小球反应，触发白细胞 浸润来自浸润细胞的促炎细胞因子诱导或 增加生长因子的产生。协同与 该网络中的拮抗元素改变了组成， 在肾小球中完善的细胞外基质的产生 硬化、间质纤维化和肾衰竭。 将建立一个全面的人IgA介导的肾病实验模型。 在T和B淋巴细胞缺陷、增殖活化中发展 基因破坏（敲除）小鼠。该模型将提供一个框架， 阐明了在体内的细胞和分子机制， 与肾小球人类伊加免疫沉积物相关。为了开发模型 并评估假设，将解决以下具体目标： 1.我们将构建人IgA 1和IgA 2抗原特异性嵌合抗体， 用于形成人伊加免疫复合物的抗体。 2.我们将阐明导致人类IgA-IC的主要机制， 肾小球定位 3.我们将鉴定肾小球对人IgA-IC反应的介质 通过检查：补体沉积、促凝血活性、表型和 基因型表达 选择素和趋化因子。 4.我们将确定促炎细胞因子的致肾炎特征， 伊加免疫沉积的肾组织中的生长因子。 5.我们将在人伊加肾病的慢性模型中描述 细胞外基质基因的差异表达参与了 肾纤维化的进展阶段 失败 这些研究将提供一个深入了解细胞和分子 伊加肾病的发病机制可能是 靶向用于开发治疗和预防进展为肾 失败