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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：
3079184
负责人：
WESTLEY H REEVES
金额：
$ 7.59万
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

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对于抗核蛋白的诱导可能很重要抗体。据推测，核蛋白具有相似的功能，例如与核酸相互作用的能力，可能包含相似的结构域，具有免疫交叉反应性。这外源（例如病毒）蛋白质中同源结构域的存在可能在克服系统性红斑狼疮的自我耐受中发挥作用，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/功能域抗原的蛋白水解解剖和使用特异性免疫学探针（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，以比较它们的与其他细胞和病毒蛋白质的基因结构； 3）使用用于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有关自身免疫发病机制和基本原理的信息调节细胞的蛋白质-核酸相互作用机制分裂和基因转录。候选人的细胞背景生物学和免疫学为计划的实施提供了适当的准备研究。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随时可以接近分子/细胞生物学和免疫学将为候选人作为独立调查员的发展。