Dysferlin regulation of acetylcholine signaling at the C. elegans NMJ
Dysferlin 对线虫 NMJ 乙酰胆碱信号传导的调节
基本信息
- 批准号:8000546
- 负责人:
- 金额:$ 5.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-06-01 至 2012-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAffectAgonistAnimal ModelAnimalsBehavioral AssayCaenorhabditis elegansCellsCholinergic ReceptorsDYSF geneDefectDevelopmentEventExhibitsFunctional disorderGenesGeneticHereditary DiseaseLeadLevamisoleLimb-Girdle Muscular DystrophiesLocomotionMediatingMembraneModelingMolecularMuscleMuscle WeaknessMuscle functionMuscular DystrophiesMutationMyopathyNeuromuscular JunctionNeuronsOrthologous GenePhenotypePlayRNA InterferenceRegulationResearchResistanceRoleSignal TransductionSiteSkeletal MuscleSynapsesSystemTestingTherapeuticUnited StatesVesiclein vivoloss of function mutationmutantnovelpromoterpublic health relevancerepairedresearch studysynaptic function
项目摘要
DESCRIPTION (provided by applicant): The muscular dystrophies, incurable genetic disorders that result in progressive muscle weakness and degeneration, affect about 250,000 people in the United States. Genetic causes of many muscular dystrophies are known, however, further understanding of muscular dystrophy pathophysiology is required to develop appropriate therapeutic strategies. Limb Girdle Muscular Dystrophy type 2B (LGMD2B) is caused by loss of function mutations in Dysferlin, which regulates vesicle fusion events to repair damaged muscle membranes. Exactly how loss of Dysferlin lead to LGMD2B phenotypes is unknown. Exciting results in C. elegans show that the Dysferlin ortholog fer-1 is expressed in body-wall muscles where it plays a novel role in synaptic function by regulating the localization of acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ). Integration of these findings with previous models of Dysferlin- mediated vesicle fusion, suggests that loss of FER-1/Dysferlin causes a reduction in AChR-containing vesicle fusion at the NMJ, leading to defects in synaptic function that may contribute to LGMD2B phenotypes. Using the model organism C. elegans, three independent lines of experimentation will be used to study this novel synaptic role of FER-1 and more broadly, the regulation of post-synaptic acetylcholine (ACh) signaling. C. elegans is a powerful genetic system used for analysis of muscle function, and the body-wall muscles which control C. elegans locomotion are functionally comparable to vertebrate skeletal muscle. Although C. elegans fer-1 is expressed in muscles, its site of action is not known. Cell-specific promoters will be used to express fer-1 in muscles or neurons in order to determine where FER-1 functions. Additional rescue experiments will be performed to determine if C. elegans fer-1 and mammalian Dysferlin are functionally orthologous in the regulation of synaptic function. Although fer-1 mutants exhibit defects in pharmacological behavioral assays and the localization of post-synaptic AChRs, the effect of loss of fer-1 on body-wall muscle activity is unknown. Thus, an in vivo electrophysiological approach will be used to determine the effect of fer-1 mutations on acetylcholine- evoked muscle currents and further define the role of C. elegans FER-1 in synaptic function. Finally, the molecular mechanisms that regulate and maintain proper post-synaptic acetylcholine (ACh) signaling are not fully understood. Additional genes that, like fer-1, are required for the modulation of ACh signaling will be identified by performing an RNA interference (RNAi) screen for animals resistant to the AChR agonist levamisole. In conclusion, I will achieve a further understanding of the molecular mechanisms underlying ACh signaling at the NMJ by testing a novel role for FER-1/Dysferlin in the regulation of synaptic function and identifying novel genes required for regulation of post-synaptic ACh signaling.
PUBLIC HEALTH RELEVANCE: Limb Girdle Muscular Dystrophy type 2B (LGMD2B), which is caused by loss of function mutations in the gene Dysferlin, results in progressive muscle weakness. Recent results suggest that loss of Dysferlin causes defects in synaptic function and this may contribute to LGMD2B phenotypes. Our research using C. elegans to study this novel pathophysiological mechanism of LGMD2B may lead to a better understanding of the molecular mechanisms that cause progressive muscle weakness and could lead to the development of new therapies to treat this incurable muscle disease.
描述(由申请人提供):肌肉营养不良症是一种无法治愈的遗传疾病,会导致进行性肌肉无力和退化,在美国约有25万人受到影响。许多肌营养不良的遗传原因是已知的,然而,需要进一步了解肌营养不良的病理生理学,以制定适当的治疗策略。2B型肢体Girdle肌营养不良症(LGMD2B)是由去铁蛋白功能突变引起的,去铁蛋白调节囊泡融合事件以修复受损的肌膜。脱铁蛋白丢失如何导致LGMD2B表型尚不清楚。在线虫中的激动人心的结果表明,deferlin的同源基因FER-1在体壁肌肉中表达,它通过调节神经肌肉接头(NMJ)上的乙酰胆碱受体(AChRs)的位置而在突触功能中发挥新的作用。将这些发现与先前的dyferlin介导的囊泡融合模型相结合,表明FER-1/dyferlin的丢失导致NMJ含有AChR的囊泡融合减少,导致突触功能缺陷,这可能与LGMD2B表型有关。利用模式生物秀丽线虫,三条独立的实验线路将被用来研究FER-1的这种新的突触作用,以及更广泛地说,对突触后乙酰胆碱(ACh)信号的调节。线虫是一种用于分析肌肉功能的强大遗传系统,控制线虫运动的体壁肌肉在功能上与脊椎动物的骨骼肌相似。尽管线虫FER-1在肌肉中表达,但其作用部位尚不清楚。细胞特异性启动子将被用来在肌肉或神经元中表达FER-1,以确定FER-1在哪里发挥作用。还将进行其他救援实验,以确定线虫FER-1和哺乳动物的deferlin在突触功能调节方面是否在功能上是同源的。尽管FER-1突变体在药理行为分析和突触后AChRs的定位方面存在缺陷,但FER-1缺失对体壁肌肉活动的影响尚不清楚。因此,我们将使用体内电生理学方法来确定FER-1突变对乙酰胆碱诱发的肌肉电流的影响,并进一步确定线虫FER-1在突触功能中的作用。最后,调节和维持适当的突触后乙酰胆碱(ACh)信号的分子机制还不完全清楚。通过对抗乙酰胆碱受体激动剂左旋咪唑的动物进行RNA干扰(RNAi)筛查,将识别出与FER-1一样,调节ACh信号所需的其他基因。综上所述,我将通过测试FER-1/dyferlin在调节突触功能中的新作用,并确定调控突触后ACh信号所需的新基因,进一步了解NMJ ACh信号的分子机制。
公共卫生相关性:2B型肢体Girdle肌营养不良症(LGMD2B)是由基因功能障碍突变引起的,导致进行性肌肉无力。最近的研究结果表明,dyferlin的缺失会导致突触功能的缺陷,这可能与LGMD2B表型有关。我们利用线虫研究LGMD2B的这种新的病理生理机制可能有助于更好地理解导致进行性肌肉无力的分子机制,并可能导致开发治疗这种不可治愈的肌肉疾病的新疗法。
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)
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Jessica E Tanis其他文献
Calcium homeostasis modulator (CALHM) ion channels: structure, functions and physiological roles.
钙稳态调节剂 (CALHM) 离子通道:结构、功能和生理作用。
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
J Kevin Foskett;Zhongming Ma;Adam P Siebert;Todd Lamitina;Philippe Marambaud;Jessica E Tanis;Akiyuki Taruno - 通讯作者:
Akiyuki Taruno
Jessica E Tanis的其他文献
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{{ truncateString('Jessica E Tanis', 18)}}的其他基金
Impact of PIP5K1 on extracellular vesicle biogenesis
PIP5K1 对细胞外囊泡生物发生的影响
- 批准号:
10666794 - 财政年份:2023
- 资助金额:
$ 5.05万 - 项目类别:
Identification of mechanisms that regulate postsynaptic receptor abundance at the neuromuscular junction
神经肌肉接头突触后受体丰度调节机制的鉴定
- 批准号:
10352307 - 财政年份:2021
- 资助金额:
$ 5.05万 - 项目类别:
Identification of mechanisms that regulate postsynaptic receptor abundance at the neuromuscular junction
神经肌肉接头突触后受体丰度调节机制的鉴定
- 批准号:
10091026 - 财政年份:2021
- 资助金额:
$ 5.05万 - 项目类别:
Elucidating biogenesis and cargo sorting mechanisms for discrete extracellular vesicle subpopulations in C. elegans
阐明线虫离散细胞外囊泡亚群的生物发生和货物分选机制
- 批准号:
10668290 - 财政年份:2020
- 资助金额:
$ 5.05万 - 项目类别:
Elucidating biogenesis and cargo sorting mechanisms for discrete extracellular vesicle subpopulations in C. elegans
阐明线虫离散细胞外囊泡亚群的生物发生和货物分选机制
- 批准号:
10223381 - 财政年份:2020
- 资助金额:
$ 5.05万 - 项目类别:
Supplement to Elucidating biogenesis and cargo sorting mechanisms for discrete extracellular vesicle subpopulations in C. elegans
补充阐明线虫离散细胞外囊泡亚群的生物发生和货物分选机制
- 批准号:
10643364 - 财政年份:2020
- 资助金额:
$ 5.05万 - 项目类别:
Elucidating biogenesis and cargo sorting mechanisms for discrete extracellular vesicle subpopulations in C. elegans
阐明线虫离散细胞外囊泡亚群的生物发生和货物分选机制
- 批准号:
10725076 - 财政年份:2020
- 资助金额:
$ 5.05万 - 项目类别:
Elucidating biogenesis and cargo sorting mechanisms for discrete extracellular vesicle subpopulations in C. elegans
阐明线虫离散细胞外囊泡亚群的生物发生和货物分选机制
- 批准号:
10456097 - 财政年份:2020
- 资助金额:
$ 5.05万 - 项目类别:
Dysferlin regulation of acetylcholine signaling at the C. elegans NMJ
Dysferlin 对线虫 NMJ 乙酰胆碱信号传导的调节
- 批准号:
8085729 - 财政年份:2010
- 资助金额:
$ 5.05万 - 项目类别:
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