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MECHANISMS OF ANTINUCLEAR ANTIBODY PRODUCTION IN SLE

SLE 中抗核抗体的产生机制

基本信息

批准号：
3079100
负责人：
WESTLEY H REEVES
金额：
$ 7.56万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-07-01 至 1990-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3079100
关键词：
antiantibody antinuclear autoantibody autoantigens autoimmune disorder cellular immunity enzyme linked immunosorbent assay genetic library genetic manipulation genetic recombination human tissue humoral immunity immunofluorescence technique molecular cloning molecular pathology monoclonal antibody nucleic acid sequence radiotracer systemic lupus erythematosus

项目摘要

One of the hallmarks of systemic lupus erythematosus (SLE) is the production of antinuclear antibodies that react with nuclear proteins and nucleoproteins. The high specificity of these autoantibodies for nuclear structures suggests that certain structural or functional characteristics of nuclear proteins might be important for the induction of antinuclear antibodies. It is hypothesized that nuclear proteins which have similar functions, such as the ability to interact with nucleic acid, might contain similar structural domains which are immunologically cross-reactive. The existence of homologous domains in foreign (e.g., viral) proteins might play a role in overcoming self-tolerance in SLE, leading to autoantibody synthesis. Three specific aims will be addressed: 1) the identification of structural/functional domains of nuclear protein autoantigens by proteolytic dissection of the antigens and by use of specific immunological probes (murine monoclonal antibodies and SLE sera); 2) molecular cloning and sequencing of DNA encoding these proteins in order to compare their gene structure with that of other cellular and viral proteins; 3) use of the structural/functional information to study the induction and regulation of antinuclear antibody systhesis. These studies may provide new information regarding both the pathogenesis of autoimmunity and the basic mechanisms of protein-nucleic acid interactions which regulate cell division and gene transcription. The candidate's background in cell biology and immunology has provided suitable preparation for the planned studies. The sponsor's expertise in molecular and cell biology will enable the candidate to gain valuable experience in these fields. The facilities as well as the ready accessibility of other highly trained investigators in molecular/cell biology and immunology will provide an ideal environment for the candidate's development as an independent investigator.

系统性红斑狼疮（SLE）的特征之一是产生与核蛋白反应的抗核抗体，核蛋白这些自身抗体对核抗原的高度特异性，结构表明某些结构或功能特征核蛋白的表达可能对诱导抗核抗体的产生起重要作用。抗体的据推测，具有类似结构的核蛋白功能，如与核酸相互作用的能力，可能包含免疫交叉反应的相似结构域。的外源同源结构域的存在（例如，病毒）蛋白质可能在克服SLE的自身耐受性中发挥作用，导致自身抗体合成. 将解决三个具体目标：1）识别核蛋白自身抗原的结构/功能域，蛋白水解分解抗原和使用特异性免疫探针（鼠单克隆抗体和SLE血清）; 2）分子克隆并对编码这些蛋白质的DNA进行测序，基因结构与其他细胞和病毒蛋白质的基因结构; 3）使用研究诱导和调节的结构/功能信息抗核抗体合成这些研究可能提供新的关于自身免疫的发病机制和基本的免疫学基础的信息。蛋白质-核酸相互作用的机制，分裂和基因转录。候选人在牢房里的背景生物学和免疫学为计划中的问题研究申办者在分子和细胞生物学方面的专业知识将使候选人在这些领域获得宝贵的经验。设施以及其他训练有素的调查人员的随时可用性，分子/细胞生物学和免疫学将提供理想的环境，候选人作为独立调查员的发展。