Genome Wide Analysis of Alpha-Synuclein Neurotoxicity
α-突触核蛋白神经毒性的全基因组分析
基本信息
- 批准号:10221064
- 负责人:
- 金额:$ 58.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-25 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelBiochemicalBiologicalBiological ModelsCellsClinicalCytoplasmic InclusionDataDefectDementia with Lewy BodiesDepositionDiffuseDiseaseDrosophila genusEquipment and supply inventoriesFunctional disorderGene DosageGenesGeneticGenetic ModelsGenetic ScreeningGenomicsHumanImpairmentLewy BodiesLewy neuritesMediatingModelingModificationMolecularMovement DisordersMultiple System AtrophyNerve DegenerationNeurodegenerative DisordersNeurogliaNeurologistNeuronsParkinson DiseaseParkinson&aposs DementiaPathogenesisPathologicPathologyPathway interactionsPatientsPhysiologicalPoint MutationPopulationProcessProteinsSomatotypeSynapsesSystemTestingTimeToxic effectalpha synucleinalpha synuclein genebasecell typeclinically significantdesigndopaminergic neuronearly onsetexperimental studygene productgenetic analysisgenetic approachgenome wide association studygenome-widegenome-wide analysisin vivoinsightnervous system disorderneuropathologyneurotoxicitynon-motor symptomnovelprotein aggregationsynucleinopathytherapeutic target
项目摘要
Parkinson's disease is the most common neurodegenerative movement disorder and is characterized
pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated α-synuclein
protein. Abnormal deposition of α-synuclein into neuronal and glial aggregates is also the primary pathologic
feature of a group of collectively even more common disorders, termed the α-synucleinopathies. To define
the molecular mechanisms controlling α-synuclein induced neurodegeneration we and others have modeled
α-synucleinopathies in the simple and powerful genetic model organism Drosophila. Genetic, biochemical
and cell biological experiments in Drosophila have provided important clues regarding the pathogenesis of
α-synucleinopathies. However, the unbiased forward genetic screens providing the bases for these studies,
while valuable, have to date remained incomplete. Here we propose to use a newly created and powerful
Drosophila model of α-synucleinopathies to perform a comprehensive genetic analysis of α-synuclein
neurotoxicity in vivo. These studies will for the first time provide a broad analysis of mechanisms controlling
α-synuclein toxicity to postmitotic neurons and should identify many new high-value therapeutic targets.
Our studies will be particularly important as more and more data emerges from genome wide associated
studies showing genetic influences on Parkinson's disease and related α-synucleinopathies, but with little
clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative
disease pathogenesis.
帕金森病是最常见的神经退行性运动障碍,
病理上通过异常磷酸化和聚集的α-突触核蛋白的神经元内沉积
蛋白α-突触核蛋白异常沉积到神经元和神经胶质聚集体中也是原发性病理性
这是一组更常见的疾病的特征,称为α-突触核蛋白病。以限定
控制α-突触核蛋白诱导的神经退行性变的分子机制,我们和其他人已经模拟了
简单而强大的遗传模式生物果蝇中的α-突触核蛋白病。遗传的,生化的
果蝇的细胞生物学实验提供了重要的线索,
α-突触核蛋白病然而,为这些研究提供基础的无偏正向遗传筛选,
虽然很有价值,但迄今仍不完整。在这里,我们建议使用一个新创建的和强大的
果蝇α-突触核蛋白病模型对α-突触核蛋白进行综合遗传分析
体内神经毒性。这些研究将首次提供一个广泛的分析机制控制
α-突触核蛋白对有丝分裂后神经元的毒性,并应确定许多新的高价值的治疗靶点。
我们的研究将特别重要,因为越来越多的数据来自基因组范围内的相关数据,
研究显示遗传对帕金森病和相关的α-突触核蛋白病的影响,但很少
这些新发现的基因产物在神经退行性疾病中的作用机制的明确证据
发病机理
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Precision Medicine on the Fly: Using Drosophila to Decipher Gene-Environment Interactions in Parkinson's Disease.
飞行精准医学:利用果蝇破译帕金森病的基因与环境相互作用。
- DOI:10.1093/toxsci/kfab060
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Sarkar,Souvarish;Feany,MelB
- 通讯作者:Feany,MelB
Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo.
- DOI:10.1186/s13024-021-00454-3
- 发表时间:2021-05-24
- 期刊:
- 影响因子:15.1
- 作者:Sarkar S;Bardai F;Olsen AL;Lohr KM;Zhang YY;Feany MB
- 通讯作者:Feany MB
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{{ truncateString('MEL B FEANY', 18)}}的其他基金
Functional analysis of glia in alpha-synucleinopathy
α-突触核蛋白病中神经胶质细胞的功能分析
- 批准号:
9460151 - 财政年份:2018
- 资助金额:
$ 58.57万 - 项目类别:
Genome Wide Analysis of Alpha-Synuclein Neurotoxicity
α-突触核蛋白神经毒性的全基因组分析
- 批准号:
9272475 - 财政年份:2017
- 资助金额:
$ 58.57万 - 项目类别:
Integrative Multi-Omic Discovery of Proximal Mechanisms Driving Age-Dependent Neurodegeneration
驱动年龄依赖性神经变性的近端机制的综合多组学发现
- 批准号:
9413689 - 财政年份:2017
- 资助金额:
$ 58.57万 - 项目类别:
Genome Wide Analysis of Alpha-Synuclein Neurotoxicity
α-突触核蛋白神经毒性的全基因组分析
- 批准号:
10021759 - 财政年份:2017
- 资助金额:
$ 58.57万 - 项目类别:
Biochemical and in vivo determinants of tau neurotoxicity
tau 神经毒性的生化和体内决定因素
- 批准号:
8885932 - 财政年份:2012
- 资助金额:
$ 58.57万 - 项目类别:
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