ELECTRON MICROSCOPY OF MYOPATHIES

该提案寻求对继续进行调查的支持 人类和实验诱发肌肉疾病的计划。这个 疾病的探讨是通过分析光学显微镜和 肌肉纤维、神经肌肉接头的超微结构反应 肌内神经和血管。研究个别疾病 系统地通过结合光镜组织化学， 免疫细胞化学，位相和电子显微镜，免疫电子 显微镜和冷冻断口电子显微镜。只要有可能， 观测结果通过形态计量学方法进行量化，并相互关联 有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导致的机制 将进一步调查神经肌肉传递的故障：在 与高电导和快速闭合有关的综合征 Achr离子通道，这一假设将被检验为传导 终板肌病和局灶性AChR缺乏症是缺陷的条件。 在ACh量子释放减少的综合征中，额外的证据 将被认为这种疾病是由于缺乏突触引起的 小泡，这可能是由于突触小泡的不足 膜结合蛋白。在推定异常的综合征中 对于ACh-AChR相互作用，将搜索任何超微结构 可能导致缩微图像的幅度减小的关联 端板电流。在乙酰胆碱受体不足和经络不足的证候中 开放时间，终板超微结构的详细分析，以及 银环蛇毒素结合部位、AChR亚基α、 Delta和epsilon，以及AChR相关的43kD蛋白将是 被执行。在最近发现的嗜酸性粒细胞增多症-肌痛综合征中， 致残性炎症性疾病现在归因于对 L色氨酸制剂的污染、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。大鼠脑微血管损伤的实验模型 培养的人内皮细胞致敏诱导的骨骼肌 将对细胞进行调查。免疫电子显微镜定位 将重新研究正常人体骨骼肌中的肌营养不良蛋白 弄清它是否与亚细胞细胞器有关 而不是质膜。在新发现的线粒体中 由于辅酶Q10缺乏引起的脑肌病，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。

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.