ELECTRON MICROSCOPY OF MYOPATHIES

肌病的电子显微镜检查

• 批准号: 2260182
• 负责人: ANDREW George ENGEL
• 金额: $ 31.13万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2260182
• 关键词: acetylcholine; antibody; autoantibody; autoimmune disorder; biopsy; bungarotoxins; cellular pathology; cholinergic receptors; complement pathway; congenital neuromuscular disorder; dermatomyositis; disease /disorder classification; dystrophin; electron microscopy; electrophysiology; eosinophilia; freeze etching; histochemistry /cytochemistry; human subject; immunochemistry; immunocytochemistry; immunoelectron microscopy; inflammation; laboratory mouse; laboratory rat; membrane activity; membrane channels; membrane proteins; membrane structure; microelectrodes; microscopy; mitochondria; monoclonal antibody; muscle cells; muscle disorder diagnosis; muscular dystrophy; myasthenia gravis; myofibrils; necrosis; neurochemistry; neuromuscular junction; neuromuscular transmission; nicotinic receptors; peripheral blood vessel disorder; phase contrast microscopy; receptor binding; synaptic vesicles; tryptophan; ubiquinone; vascular endothelium

This proposal seeks support for the continuation of an investigative program of human and experimentally induced muscle diseases. The diseases are approached through analysis of the light microscopic and ultrastructural reactions of the muscle fiber, neuromuscular junction, intramuscular nerves and blood vessels. Individual diseases are studied systematically by combined light microscopic histochemistry, immunocytochemistry, phase and electron microscopy, immunoelectron microscopy and freeze-fracture electron microscopy. Whenever possible, the observations are quantitated by morphometric methods and correlated with available physiologic and biochemical data. In four newly recognized congenital myasthenic syndromes the mechanisms that lead to failure of neuromuscular transmission will be further investigated: In the syndrome associated with high conductance and fast closure of the AChR ion channel, the hypothesis will be tested that the transmission defect is conditioned by an endplate myopathy and focal AChR deficiency. In the syndrome with decreased release of ACh quanta, additional evidence will be sought that the disorder stems from a paucity of synaptic vesicles and that this could be due to a deficiency of a synaptic vesicle membrane associated protein. In the syndrome with a putative abnormality of ACh-AChR interaction, a search will be made for any ultrastructural correlate that might result in a reduced amplitude of the miniature endplate current. In the syndrome of AChR deficiency and short channel open time, detailed analysis of endplate ultrastructure, and of the distribution of alpha-bungarotoxin binding sites, AChR subunits alpha, delta and epsilon, and of the AChR-associated 43 kD protein will be carried out. In the recently recognized eosinophilia-myalgia syndrome, a disabling inflammatory disease now attributed to sensitization to a contaminant of L-tryptophan preparations, immunocytochemical and ultrastructural studies will be done to define immune effector mechanisms and their targets. An experimental model of microvascular injury to skeletal muscle induced by sensitization to cultured human endothelial cells will be investigated. The immunoelectron microscopic localization of dystrophin in normal human skeletal muscle will be reinvestigated to clarify whether it is, or is not, associated with subcellular organelles other than the plasma membrane. In the newly discovered mitochondrial encephalomyopathy due to coenzyme Q10 deficiency, the hypothesis will be tested that the disorder is caused by a defect in the mitochondrial biosynthesis of coenzyme Q10.

这项建议寻求支持继续进行调查， 人类和实验诱导的肌肉疾病的程序。 的 疾病是通过分析光显微镜和 肌纤维，神经肌肉接头， 肌肉神经和血管。 研究了个别疾病 系统地结合光镜组织化学， 免疫细胞化学、相和电子显微镜、免疫电子 显微镜和冷冻断裂电子显微镜。 只要有可能， 通过形态测量方法对观察结果进行定量， 与可用的生理和生化数据。 在四个新的 公认的先天性肌无力综合征的机制，导致 神经肌肉传递的失败将进一步研究： 与高传导性和快速闭合相关的综合征 AChR离子通道的假设将被检验， 缺陷的条件是终板肌病和局灶性AChR缺乏。 在ACh量子释放减少的综合征中， 将寻求这种疾病源于缺乏突触， 小泡，这可能是由于缺乏突触小泡 膜相关蛋白 在假定异常的综合征中， ACh-AChR相互作用，将搜索任何超微结构 可能导致微缩模型振幅降低的相关性 终板电流 AChR缺乏和短通道综合征 开放时间，详细分析终板超微结构， α-银环蛇毒素结合位点，AChR亚基α， δ和β，以及AChR相关的43 kD蛋白质将被 贯彻 在最近发现的嗜酸性粒细胞增多症-肌痛综合征中， 致残的炎症性疾病现在归因于对一种 L-色氨酸制剂的污染物，免疫细胞化学和 将进行超微结构研究以确定免疫效应机制 和他们的目标 微血管损伤的实验模型 培养人内皮细胞致敏骨骼肌 细胞将被研究。 免疫电镜定位 将重新研究正常人骨骼肌中抗肌萎缩蛋白的含量， 阐明它是否与亚细胞器有关 除了细胞膜。 在新发现的线粒体中 脑肌病由于辅酶Q10缺乏，假设将是 测试表明，这种疾病是由线粒体缺陷引起的， 辅酶Q10的生物合成。