Congenital Myasthenic Syndromes

先天性肌无力综合症

基本信息

批准号：
10087975
负责人：
ANDREW George ENGEL
金额：
$ 44.38万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10087975
关键词：
3&apos Untranslated Regions Acetylcholine Address Adrenergic Agents Affect Affinity Agrin Binding Binding Sites Biochemical Candidate Disease Gene Cations Cholinergic Agonists Cholinergic Receptors Clinical Complex Congenital Myasthenic Syndromes Coupling Defect Diagnosis Disease Electrophysiology (science)Engineering Environment Event Functional disorder Genes Genetic Hydrophobic Interactions Hydrophobicity In Vitro Investigation Kinetics Knowledge Length Maintenance MicroRNAs Molecular Morphology Muscle Mutagenesis Mutate Mutation Myasthenia Nerve Neurobiology Nonsense Mutation Outcome Patients Phenotype Prevention Probability Proteins Reporting Rest SNAP receptor Safety Structure Synapses Syndrome System Testing Time UNC13B gene Variant Work base channel blockers clinical phenotype disabling disease exome exome sequencing fetal gene product genome sequencing hydrophilicity improved insight muscle strength mutant neuromuscular transmission novel protein function quantum receptor expression response transcriptome sequencing whole genome

项目摘要

PROJECT SUMMARY Support is requested for a multifaceted investigation of congenital myasthenic syndromes (CMS). The CMS are heterogeneous and disabling diseases in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanism(s). We will use the candidate gene approach combined with whole exome sequencing to find the cause of different CMS, determine the mechanism by which the mutant gene causes the CMS, and then use this information to generate structure-function correlations and devise strategies for therapy. The candidate gene approach rests on determining (1) the clinical phenotype, (2) the morphologic phenotype based on cytochemical and ultrastructural features of the endplate (EP), (3) the number of acetylcholine (ACh) receptors (AChRs) per EP, (4) the electrophysiologic phenotype reflected by parameters of neuromuscular transmission in vitro. The mechanism by which the mutant gene causes a CMS is investigated by engineering the mutant and corresponding wild-type gene into a suitable expression system which is then interrogated by appropriate electrophysiologic and biochemical tests. Structure–function correlations rest on further mutagenesis studies and on analysis of the mechanism by which a change in the structure of the mutated protein alters the function of that protein, and how this alteration affects the safety margin of neuromuscular transmission. Strategies for therapy are based on determining the molecular defect caused by the mutation and whether the identified defect increases or decreases the synaptic response to ACh.

项目摘要要求对先天性肌关系综合征（CMS）进行多方面的支持。 CMS 神经肌肉传播的安全边缘是异质性和致残性疾病被一种或多种特定机制所妥协。我们将使用候选基因方法与整个外显子组测序以找到不同CM的原因，确定突变体的机制基因引起CMS，然后使用此信息来生成结构功能相关性并设计治疗策略。候选基因方法取决于（1）临床表型，（2）形态学表型基于终板的细胞化学和超微结构特征（EP），（3）乙酰胆碱的数量（ACH）的数量每EP受体（ACHR），（4）由神经肌肉参数反映的电生理表型体外传播。突变基因引起CMS的机制通过工程研究了突变体和相应的野生型基因成合适的表达系统，然后被审问适当的电生理和生化测试。结构 - 功能相关性进一步取决于诱变研究和分析突变结构变化的机制蛋白质改变该蛋白质的功能，以及这种改变如何影响神经肌肉的安全缘传播。治疗策略基于确定由突变引起的分子缺损以及确定的缺陷是否增加还是减少对ACH的突触反应。