OCULAR MUSCLE INVOLVEMENT BY MYASTHENIA GRAVIS

重症肌无力对眼肌的影响

• 批准号: 2444236
• 负责人: HENRY J KAMINSKI
• 金额: $ 8.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2444236
• 关键词: SDS polyacrylamide gel electrophoresis; antibody specificity; chimeric proteins; disease /disorder model; electrophysiology; enzyme linked immunosorbent assay; extraocular muscle; genetic library; human tissue; immunocytochemistry; in situ hybridization; laboratory rat; model design /development; myasthenia gravis; nicotinic receptors; nucleic acid sequence; protein structure function; receptor binding; receptor expression; western blottings

Myasthenia gravis (MG) is an autoimmune disease, caused by antibodies directed at the skeletal muscle nicotinic acetylcholine receptor. MG continues to be a significant cause of impaired vision despite advances in treatment and understanding of its pathophysiology. Weakness of extraocular muscle (EOM) occurs in about 90 percent of myasthenics and 15 percent of all myasthenics will only manifest ocular signs. Why EOM is affected more prominently than extremity muscle is not understood. We hypothesize that EOM is preferentially affected by the autoimmune process because it contains unique epitopes which are differentially targeted for auto-immune mediated damage by MG. Unlike extremity skeletal muscle, mammalian EOM contains multiply-innervated fibers. Dr. Kenichiro Oda has identified antibodies from ocular myasthenics' sera whiCh bind exclusively to the endplate region of the multiply-innervated fibers. In Phase 1 of the training program, we will use Dr. Oda's antibodies to screen a human EOM cDNA expression library to identify fusion proteins which bind these antibodies. DNA sequences of the fusion proteins will be analyzed for similarities to known acetylcholine receptor subunits and endplate proteins. In Phase 2 of the research plan, the pathogenic nature of these proteins will be assessed by development of an enzyme-linked immunosorbent assay for ocular and generalized MG and animal model of ocular MG. The research program offers an ideal training program for the Principal Investigator, Dr. Kaminski. Phase 1 serves to teach fundamental molecular biological techniques, while Phase 2 leads to application of these methods to an important clinical problem. The long term goals of this project are to develop new treatment modalities for MG and improved understanding of the EOM function.

重症肌无力 (MG) 是一种由抗体引起的自身免疫性疾病 针对骨骼肌烟碱乙酰胆碱受体。 MG 尽管在这方面取得了进步，但仍然是视力受损的一个重要原因 治疗和了解其病理生理学。弱点 约 90% 的肌无力患者会出现眼外肌 (EOM) 症状，而 15% 的肌无力患者会出现眼外肌 (EOM) 症状 百分之百的肌无力患者只会出现眼部症状。为什么 EOM 是 比四肢肌肉受影响更显着的情况尚不清楚。我们 假设 EOM 优先受自身免疫过程影响 因为它包含针对不同目标的独特表位 MG 介导的自身免疫损伤。与四肢骨骼肌不同， 哺乳动物 EOM 含有多神经支配纤维。尾田健一郎博士 从眼部肌无力患者的血清中鉴定出专门结合的抗体 到多神经支配纤维的终板区域。在第一阶段 培训计划中，我们将使用小田博士的抗体来筛选人类 EOM cDNA 表达文库，用于鉴定结合这些的融合蛋白 抗体。将分析融合蛋白的 DNA 序列 与已知的乙酰胆碱受体亚基和终板的相似性 蛋白质。在研究计划的第二阶段，这些疾病的致病性质 将通过开发酶联免疫吸附剂来评估蛋白质 眼部和全身性 MG 测定以及眼部 MG 动物模型。 该研究计划为校长提供了理想的培训计划 研究员卡明斯基博士。第一阶段用于教授基础分子 生物技术，而第二阶段导致这些方法的应用 到一个重要的临床问题。该项目的长期目标是 开发 MG 的新治疗方式并提高对 MG 的认识 EOM 功能。