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MYOSIN--A LINK BETWEEN STREPTOCOCCI AND HEART

肌球蛋白——链球菌和心脏之间的纽带

基本信息

批准号：
7357487
负责人：
MADELEINE W. CUNNINGHAM
金额：
$ 34.73万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-08-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7357487
关键词：
Acute Animal Disease Models Animal Model Animals Antibodies Antigenic Specificity Antigens Arthritis Autoantibodies Autoimmune Process Autoimmunity Base Sequence Behavior Biology Cardiac Myosins Carditis Cell Line Characteristics Child Chorea Data Deposition Development Disease Endothelial Cells Epitopes Genes Goals Heart Human Hybridomas Immunization Immunoglobulin G Immunoglobulin M Infectious Agent Investigation Light Link Modeling Molecular Mimicry Monoclonal Antibodies Mus Myosin ATPase Nature Pathogenesis Play Polymerase Chain Reaction Production Proteins Rattus Recombinants Rheumatic Fever Rheumatic Heart Disease Role Serum Somatic Mutation Streptococcal Infections Streptococcus Streptococcus pyogenes T-Cell Immunologic Specificity T-Lymphocyte Techniques Testing Tissues Transgenes Transgenic Animals Transgenic Mice Umbilical cord structure cytokine cytotoxic cytotoxicity human monoclonal antibodies human tissue in vivo man research study transgene expression

项目摘要

Rheumatic fever is a sequela of group A streptococcal infection primarily in children. Manifestations of the disease include carditis, arthritis and chorea. Our hypothesis is that autoimmune mechanisms due to molecular mimicry between the group A streptococcus and human tissues are responsible for the disease. Our data support this hypothesis. We have identified host and streptococcal antigens which react with anti-strep/heart antibodies and T cells, and we have identified streptococcal and human cardiac myosin epitopes which produce carditis and valvulitis in animal models of disease. Despite our progress, we do not know how these crossreactive autoantibodies function in the pathogenesis of acute rheumatic fever(ARF) or the exact nature and antigenic specificities of the T cells in rheumatic carditis. Therefore, the goal and objectives propose to answer questions about the potential role of antibody in disease and to investigate the nature of the T cells which are crossreactive and appear to be responsible for valvulitis. The objectives are 1) to produce a panel of cytotoxic/crossreactive monoclonal antibodies (mAbs) from humans and transgenic mice and passively transfer IgM and IgG mAbs to test for tissue deposition in vivo; 2) to determine the nucleotide sequences of crossreactive antibody V, D, and J region genes; 3) to produce transgenic mice containing the VDJ genes(H &L) of human and mouse crossreactive and/or cytotoxic mAbs; 4) to investigate the Lewis rat model of valvulitis by producing and characterizing T cell clones from rats immunized with rM6 protein and cardiac myosin and in passive transfer experiments determine if these T cells produce disease; 5) to compare valves immunohistochemically from rheumatic carditis and Lewis rat valvulitis to identify similarities. These studies will attempt to define the steps in the pathogenesis of rheumatic carditis and will continue to support the growing body of evidence that infectious agents play a role inthe development of autoimmunity inman. $ R37

风湿热是 A 族链球菌感染的后遗症，主要发生在儿童中。表现形式这些疾病包括心脏病、关节炎和舞蹈病。我们的假设是，自身免疫机制是由于 A 族链球菌和人体组织之间的分子模拟是造成这种疾病的原因。我们的数据支持这一假设。我们已经鉴定出与以下物质发生反应的宿主和链球菌抗原：抗链球菌/心脏抗体和 T 细胞，我们已经鉴定出链球菌和人心肌肌球蛋白在疾病动物模型中产生心脏炎和瓣膜炎的表位。尽管我们取得了进步，但我们仍然不知道这些交叉反应性自身抗体在急性风湿病的发病机制中如何发挥作用发烧 (ARF) 或风湿性心脏病中 T 细胞的确切性质和抗原特异性。所以，目的和目标旨在回答有关抗体在疾病和疾病中的潜在作用的问题研究具有交叉反应性且似乎与瓣膜炎有关的 T 细胞的性质。目标是 1) 生产一组细胞毒性/交叉反应性单克隆抗体 (mAb) 人类和转基因小鼠并被动转移 IgM 和 IgG mAb 以测试组织沉积体内； 2)确定交叉反应性抗体V、D、J区基因的核苷酸序列； 3）到产生含有人类和小鼠交叉反应的 VDJ 基因（H＆L）的转基因小鼠和/或细胞毒性单克隆抗体； 4) 通过产生和表征T细胞来研究Lewis大鼠瓣膜炎模型来自用 rM6 蛋白和心肌肌球蛋白免疫的大鼠的克隆以及被动转移实验确定这些 T 细胞是否会产生疾病； 5) 对风湿性瓣膜进行免疫组织化学比较心肌炎和Lewis大鼠瓣膜炎有相似之处。这些研究将尝试定义以下步骤：风湿性心脏炎的发病机制并将继续支持越来越多的证据感染因子在人类自身免疫的发展中发挥作用。 $ R37