MECHANISMS OF ANTINUCLEAR ANTIBODY PRODUCTION IN SLE

SLE 中抗核抗体的产生机制

• 批准号: 3079181
• 负责人: WESTLEY H REEVES
• 金额: $ 7.57万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 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/3079181
• 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

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和 核蛋白。这些自身抗体对核的高度特异性 Structures指某些结构或功能特征 核蛋白可能在抗核诱导中起重要作用。 抗体。假设具有相似结构的核蛋白 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。这个 外源(如病毒)蛋白中同源结构域的存在可能 在克服系统性红斑狼疮自身耐受中发挥作用，导致自身抗体 综合。将解决三个具体目标：1)识别 核蛋白自身抗原结构/功能结构域的研究 蛋白水解法分离抗原并使用特定的免疫学方法 探针(鼠单抗和SLE血清)；2)分子克隆 并对编码这些蛋白质的DNA进行测序，以便比较它们的 基因结构与其他细胞和病毒蛋白的基因结构；3)使用 研究诱导和调控的结构/功能信息 抗核抗体的合成。这些研究可能会提供新的 关于自身免疫的发病机制和基本的 蛋白质-核酸相互作用调节细胞的机制 分裂和基因转录。候选人在牢房中的背景 生物学和免疫学已经为计划中的 学习。赞助商在分子和细胞生物学方面的专业知识将使 在这些领域获得宝贵经验的候选人。这些设施 以及其他训练有素的调查人员在 分子/细胞生物学和免疫学将为 候选人作为一名独立调查员的发展。