CONGENITAL MYASTHENIC SYNDROMES

先天性肌无力综合症

• 批准号: 2668878
• 负责人: ANDREW George ENGEL
• 金额: $ 29.6万
• 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 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2668878
• 关键词: acetylcholine; acetylcholinesterase; chemical kinetics; congenital neuromuscular disorder; electromyography; gene mutation; immunocytochemistry; membrane potentials; microelectrodes; neuromuscular junction; neuromuscular transmission; nicotinic receptors; polymerase chain reaction; protein structure function; receptor expression; single strand conformation polymorphism; structural genes; voltage /patch clamp

DESCRIPTION: (Adapted from investigator's abstract) The broad aim of this proposal is to examine pathologic mechanisms in congenital myasthenic syndromes (CMS). The CMS are highly disabling disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanism(s). The CMS are not uncommon but are seldom diagnosed or treated correctly. Appropriate morphologic and electrophysiologic analysis, however, can identify the defects involved. Furthermore, such studies can implicate a candidate mutant protein or gene; for example, the electrophysiologic identification of a kinetic abnormality of AChR is presumptive evidence for a mutation in an AChR subunit. The approach to the CMS will be through five steps: (1) clinical assessment, including electromyography and tests for anti- AchR antibodies; (2) morphologic assessment, including cytochemical or immunocytochemical localization of acetylcholinesterase, AChR, and AChR subunits at the endplate (EP), estimate of the number of AChR per EP, quantitative ultrastructural analysis of the EP, and evaluation of the density and distribution of AChR on the junctional folds; (3) electrophysiologic assessment, consisting of conventional microelectrode studies of EP potentials and currents, estimates of parameters of quantal release, and evaluation of AChR channel kinetics through noise analysis and single channel patch-clamp recordings; (4) mutational analysis of AChR subunits when a kinetic abnormality of AChR is recognized; and (5) collaborative expression studies using genetically engineered mutant AChR when an AChR subunit mutation is identified. The proposed studies are important for diagnosis, treatment and prevention of the CMS; and for gaining additional insights into synaptic function and structure-function relationships of AChR. Moreover, recognition of spontaneous mutations in the EP nicotinic AChR should spur the search for mutations in neuronal nicotinic AChRs and other ligand-gated channels in various neurologic and psychiatric disorders.

描述：（改编自研究者的摘要）的广泛目标 该提案旨在检查先天性心脏病的病理机制 肌无力综合征（CMS）。 CMS 是高度致残的疾病 神经肌肉传递的安全裕度受到以下因素的影响 一种或多种特定机制。 CMS 并不罕见，但 很少得到正确诊断或治疗。 适当的形态和 然而，电生理分析可以识别所涉及的缺陷。 此外，此类研究可能暗示候选突变蛋白或 基因;例如，动力学的电生理学识别 AChR 异常是 AChR 突变的推定证据 亚基。 CMS 的方法将通过五个步骤：(1) 临床评估，包括肌电图和抗 AchR 测试 抗体； (2) 形态学评估，包括细胞化学或 乙酰胆碱酯酶、AChR 和 AChR 的免疫细胞化学定位 终板 (EP) 的亚基，每个 EP 的 AChR 数量估计， EP 的定量超微结构分析和评估 连接褶皱上 AChR 的密度和分布； (3) 电生理评估，包括传统的微电极 EP 电位和电流的研究，参数的估计 量子释放以及通过噪声评估 AChR 通道动力学 分析和单通道膜片钳记录； (4)突变型 当AChR动力学异常时AChR亚基的分析 认可； (5)利用基因技术进行协作表达研究 当鉴定出 AChR 亚基突变时，工程化突变 AChR。 这 拟议的研究对于诊断、治疗和预防很重要 CMS 的；以及获得对突触功能的更多见解 以及AChR的结构-功能关系。 此外，认可 EP 烟碱 AChR 的自发突变应该会刺激寻找 神经元烟碱 AChR 和其他配体门控通道的突变 各种神经和精神疾病。