ELECTRON MICROSCOPY OF MYOPATHIES

该提案寻求支持继续调查 人类和实验诱发的肌肉疾病的计划。 的 通过光学显微镜分析来治疗疾病 肌纤维、神经肌肉接头的超微结构反应， 肌内神经和血管。 研究个体疾病 通过结合光学显微组织化学系统地， 免疫细胞化学、相差和电子显微镜、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并进行相关 具有可用的生理和生化数据。 新四中 认识到先天性肌无力综合征的机制 神经肌肉传递失败将进一步研究： 与高电导和快速闭合相关的综合征 AChR 离子通道，将测试传输的假设 该缺陷是由终板肌病和局灶性 AChR 缺陷引起的。 在乙酰胆碱量子释放减少的综合征中，额外的证据 将寻求该疾病源于突触缺乏 囊泡，这可能是由于突触囊泡的缺乏 膜相关蛋白。 在具有假定异常的综合征中 的 ACh-AChR 相互作用，将搜索任何超微结构 关联可能会导致微型的幅度减小 端板电流。 AChR 缺乏和短通道综合征 开放时间，终板超微结构的详细分析，以及 α-银环蛇毒素结合位点、AChR 亚基 α 的分布， δ 和 epsilon，以及 AChR 相关 43 kD 蛋白的 进行。 在最近发现的嗜酸性粒细胞增多-肌痛综合征中， 致残性炎症性疾病现在归因于对某种物质的敏感性 L-色氨酸制剂、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 以及他们的目标。 微血管损伤实验模型 对培养的人内皮细胞敏感诱导的骨骼肌 细胞将被研究。 免疫电镜定位 正常人骨骼肌中肌营养不良蛋白的含量将被重新研究 澄清它是否与亚细胞器相关 除质膜外。 在新发现的线粒体中 由于辅酶 Q10 缺乏而导致的脑肌病，假设是 测试表明该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.