CCDC78 and the Pathogenesis of Centronuclear Myopathy
CCDC78 与中心核肌病的发病机制
基本信息
- 批准号:8768983
- 负责人:
- 金额:$ 5.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Splice SiteBindingBiochemicalBiopsyCell NucleusCentronuclear myopathyChildhoodChimeric ProteinsChromosome MappingCo-ImmunoprecipitationsComplementary DNACouplingDataDevelopmentDiseaseDominant-Negative MutationEvaluationFamilyFigs - dietaryFutureGene ExpressionGene MutationGenesGeneticGoalsHematoxylin and Eosin Staining MethodImage AnalysisImmunoprecipitationIn VitroKnowledgeLifeMediatingModelingMorbidity - disease rateMotorMuscleMuscle DevelopmentMuscle WeaknessMuscle functionMutateMutationMyopathyPathogenesisPathologicProductionPropertyProteinsProteomicsRoleSarcoplasmic ReticulumSkeletal MuscleStaining methodStainsTechniquesTestingWorkZebrafishcDNA Expressioncombinatorialdisabilityeffective therapyexomeexome sequencinggenetic linkage analysisgenetic pedigreein vivoloss of functionmortalitymuscular structuremutantnext generation sequencingnovelprobandprotein functiontherapy development
项目摘要
DESCRIPTION (provided by applicant): Centronuclear myopathies are a group of childhood onset muscle diseases defined by shared muscle biopsy features and characterized by muscle weakness and severe motor disability. Currently there are 5 known genetic causes for CNM, and recent studies on these gene products have identified abnormal excitation- contraction coupling as a key aspect of disease pathogenesis. Despite these advancements, no treatments current exist for CNMs and much remains to be understood about these clinically severe conditions. Approximately 40% of cases of CNM are genetic unresolved. Determination of additional genetic causes is critical to advance the knowledge of and to develop treatments for this disease. We have used linkage analysis and whole exome sequencing to identify a novel gene mutation in the CCDC78 gene in a family with autosomal dominant CNM. CCDC78 encodes a previously uncharacterized gene product, and the gene mutation is predicted to result in production of a protein with an internal deletion. Our hypotheses are that (a) wild type CCDC78 is required for muscle development and in particular for stabilizing the excitation-contraction coupling machinery and that (b) mutant CCDC78 functions in a dominant negative manner to sequester ECC proteins and thereby impair motor function. These hypotheses will be tested in two aims. Aim 1 will examine the function(s) of wild type CCDC78 and Aim 2 will test the impact of the CCDC78 mutation on muscle development and function. Both aims will utilize a combinatorial approach that includes in vitro studies, biochemical and proteomic techniques, and in vivo experimentation in the zebrafish. In particular, the project will take advantage of the
power in the zebrafish for manipulation of gene expression, used to create both loss of function and dominant negative models, and live image analysis, used to dynamically examine specific properties of muscle function. In all, this proposal will determine the function of CCDC78 in muscle development as well as the pathogenic mechanisms underlying its mutation in CNM. These data will be placed in the context of the existing knowledge of CNM, allowing for critical advancements in the understanding of muscle function and the pathogenesis of this devastating disease.
描述(由申请人提供):核中性肌病是一组儿童期发病的肌肉疾病,由共同的肌肉活检特征定义,以肌肉无力和严重的运动障碍为特征。目前已知CNM有5种遗传原因,最近对这些基因产物的研究发现异常的兴奋-收缩耦合是疾病发病的一个关键方面。尽管取得了这些进展,但目前还没有针对CNMs的治疗方法,而且这些临床严重疾病仍有许多有待了解的地方。大约40%的CNM病例是遗传未解决的。确定其他遗传原因对于提高对该病的认识和开发治疗方法至关重要。我们使用连锁分析和全外显子组测序来鉴定常染色体显性CNM家族中CCDC78基因的新基因突变。CCDC78编码一种以前未被表征的基因产物,该基因突变预计会导致产生一种内部缺失的蛋白质。我们的假设是:(a)野生型CCDC78是肌肉发育所必需的,特别是稳定兴奋-收缩耦合机制;(b)突变型CCDC78以主要的消极方式隔离ECC蛋白,从而损害运动功能。这些假设将在两个方面得到检验。目的1将检查野生型CCDC78的功能,目的2将测试CCDC78突变对肌肉发育和功能的影响。这两个目标将利用组合方法,包括体外研究,生化和蛋白质组学技术,以及斑马鱼体内实验。特别是,该项目将利用
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JAMES J DOWLING其他文献
JAMES J DOWLING的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JAMES J DOWLING', 18)}}的其他基金
AAV mediated gene knockdown of PIK3C2B as a therapeutic strategy for X-linked myotubular myopathy and fatty liver disease
AAV 介导的 PIK3C2B 基因敲低作为 X 连锁肌管肌病和脂肪肝的治疗策略
- 批准号:
10753786 - 财政年份:2023
- 资助金额:
$ 5.13万 - 项目类别:
Environmental and Epigenetic Modifiers of Susceptibility to Malignant Hyperthermia and Environmental Heat Stroke
恶性高热和环境中暑易感性的环境和表观遗传因素
- 批准号:
10606166 - 财政年份:2022
- 资助金额:
$ 5.13万 - 项目类别:
Pathophysiology and Treatment of Recessive RYR1 Related Myopathy
隐性 RYR1 相关肌病的病理生理学和治疗
- 批准号:
10405495 - 财政年份:2020
- 资助金额:
$ 5.13万 - 项目类别:
Pathophysiology and Treatment of Recessive RYR1 Related Myopathy
隐性 RYR1 相关肌病的病理生理学和治疗
- 批准号:
10640863 - 财政年份:2020
- 资助金额:
$ 5.13万 - 项目类别:
Pathophysiology and Treatment of Recessive RYR1 Related Myopathy
隐性 RYR1 相关肌病的病理生理学和治疗
- 批准号:
10224943 - 财政年份:2020
- 资助金额:
$ 5.13万 - 项目类别:
CCDC78 and the pathogenesis of centronuclear myopathy
CCDC78与中心核肌病的发病机制
- 批准号:
8288935 - 财政年份:2012
- 资助金额:
$ 5.13万 - 项目类别:
相似海外基金
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10797554 - 财政年份:2023
- 资助金额:
$ 5.13万 - 项目类别:
Quantitative and Predictive Analysis of 5' Splice Site Recognition by U1 snRNP using Massively Parallel Arrays
使用大规模并行阵列对 U1 snRNP 5 剪接位点识别进行定量和预测分析
- 批准号:
10460136 - 财政年份:2021
- 资助金额:
$ 5.13万 - 项目类别:
Quantitative and Predictive Analysis of 5' Splice Site Recognition by U1 snRNP using Massively Parallel Arrays
使用大规模并行阵列对 U1 snRNP 5 剪接位点识别进行定量和预测分析
- 批准号:
10311645 - 财政年份:2021
- 资助金额:
$ 5.13万 - 项目类别:
Uncovering Mechanisms of 5' Splice Site Fidelity
揭示 5 剪接位点保真度的机制
- 批准号:
10532793 - 财政年份:2020
- 资助金额:
$ 5.13万 - 项目类别:
Mechanism of Splice Site Recognition by the U2AF/SF1 Protein Complex
U2AF/SF1 蛋白复合物的剪接位点识别机制
- 批准号:
553974-2020 - 财政年份:2020
- 资助金额:
$ 5.13万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
How do RNA-binding proteins control splice site selection?
RNA 结合蛋白如何控制剪接位点选择?
- 批准号:
BB/T000627/1 - 财政年份:2020
- 资助金额:
$ 5.13万 - 项目类别:
Research Grant
Uncovering Mechanisms of 5' Splice Site Fidelity
揭示 5 剪接位点保真度的机制
- 批准号:
10316181 - 财政年份:2020
- 资助金额:
$ 5.13万 - 项目类别:
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10769989 - 财政年份:2019
- 资助金额:
$ 5.13万 - 项目类别:
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10808389 - 财政年份:2019
- 资助金额:
$ 5.13万 - 项目类别:
Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
- 批准号:
10585911 - 财政年份:2019
- 资助金额:
$ 5.13万 - 项目类别: