NEPHRITOGENIC EPITOPES IN GOODPASTURES SYNDROME

Goodpastures 综合征中的肾源性表位

• 批准号: 2838193
• 负责人: Warren Kline BOLTON
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2838193
• 关键词: Goodpasture's syndrome; antigens; basement membrane; chimeric proteins; collagen; epitope mapping; gene expression; glomerulonephritis; high performance liquid chromatography; laboratory rat; mass spectrometry; pathologic process; posttranslational modifications; protein sequence

Description (Adapted from Investigator's Abstract): Glomerulonephritis in man is a major cause of morbidity, mortality and end stage renal disease (ESRD) leading to dialysis or transplantation. Autoimmune disease causes most forms of glomerulonephritis. Multiple pathogenic factors are involved in the final expression of glomerulonephritis including the deposition of antibodies and cell mediated immunity. Numerous models have been extensively studied to clarify pathogenic mechanisms, but most likely are induced by methods not directly relevant to man. This investigator has developed a model to examine the pathogenesis of Goodpasture's syndrome, a disease associated with antibody to the glomerular basement membrane, progressive crescentic glomerulonephritis and pulmonary hemorrhage. His studies suggest that a variety of antibodies develop after immunization with the responsible antigen, and that only a subset of these antibodies actually cause disease. Post-translational modification may be critical for expression of the pathogenic antigen. The PI hypothesizes that post-transcriptional modification of the amino acids constituting the immunizing antigen influences its ability to cause nephritis. The specific aims are to utilize biochemical and molecular methods to 1) identify the antigens which induce the glomerulonephritis, 2) determine if post-translational modification of the amino acids are present and what these modifications might be, and 3) examine the effect of alternation of these modifications on disease induction and course. Strong evidence indicates that the antigen which causes glomerulonephritis in this model is the same antigen or is located on the same protein that causes Goodpasture's syndrome in man. This model provides an opportunity for further study of pathogenic events in autoimmune glomerulonephritis and permits investigations of pathogenesis that cannot be accomplished in vitro. Information derived from this model will provide a better understanding of Goodpasture's syndrome and other types of autoimmune glomerulonephritis. Further, the knowledge resultant from these investigations may provide a basis for the eventual development of specific therapeutic interventions for Goodpasture's syndrome.

描述（根据研究者的摘要改编）：人肾小球肾炎是发病，死亡率和终阶段肾脏疾病（ESRD）的主要原因，导致透析或移植。自身免疫性疾病会导致大多数形式的肾小球肾炎。多种致病因素参与肾小球肾炎的最终表达，包括抗体的沉积和细胞介导的免疫力。已经对许多模型进行了广泛的研究以阐明致病机制，但很可能是由与人无直接相关的方法引起的。该研究者开发了一个模型来检查Goodpasture综合征的发病机理，该疾病与肾小球基底膜，进行性新月形肾小球肾炎和肺出血有关的疾病。他的研究表明，用负责任的抗原免疫后会出现多种抗体，并且只有这些抗体的一部分实际上会引起疾病。翻译后修饰对于表达致病性抗原可能至关重要。 PI假设构成免疫抗原的氨基酸的转录后修饰会影响其引起肾炎的能力。具体目的是利用生化和分子方法1）确定诱导肾小球肾炎的抗原，2）确定是否存在氨基酸的翻译后修饰，以及这些修饰可能是什么，以及3）检查这些修饰对疾病诱导和过程的影响。有力的证据表明，在该模型中引起肾小球肾炎的抗原是相同的抗原，或者位于同一蛋白质上，导致人类的综合综合征。该模型为自身免疫性肾小球肾炎中的致病事件进一步研究提供了一个机会，并允许对无法在体外完成的发病机理进行研究。从该模型中得出的信息将更好地了解Goodpasture综合征和其他类型的自身免疫性肾小球肾炎。此外，这些研究的知识可能为最终开发了对Goodpasture综合征的特定治疗干预措施的基础。