PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
PINK1 对神经元和线粒体稳态的调节
基本信息
- 批准号:8501035
- 负责人:
- 金额:$ 31.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-15 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAutophagocytosisCell LineCellsCellular biologyDataDiseaseDisease modelGeneticGoalsHarvestHomeostasisHumanImmunochemistryIn VitroInjuryIntoxicationKnock-in MouseKnockout MiceKnowledgeLightLinkMAP1 Microtubule-Associated ProteinMass Spectrum AnalysisMediatingMediator of activation proteinMitochondriaModelingMorphologyMusMutationNerve DegenerationNeuritesNeurodegenerative DisordersNeuronal DysfunctionNeuronal InjuryNeuronsOrganellesPTEN geneParkinson DiseaseParkinsonian DisordersPathway interactionsPhosphorylationPhosphorylation SitePhosphotransferasesProcessProteinsProteomicsRecessive Parkinsonism, AutosomalRecombinantsRegulationRoleSignal PathwaySiteStressSynapsesSystemTestingTherapeuticToxinbrain tissuein vivoinsightleucine-rich repeat kinase 2loss of function mutationmitochondrial autophagymitochondrial dysfunctionmutantneuroprotectionnovelnovel therapeuticsoverexpressionpreventtherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Mutations in PTEN-induced kinase 1 (PINK1) are associated with autosomal recessive parkinsonism. Early studies have uniformly shown a neuroprotective role for PINK1, indicating that studying this familial form of Parkinson's Disease (PD) may offer valuable insights into potential therapeutic strategies. Dysregulation of mitochondria and autophagy are each centrally implicated in toxin, genetic and environmental approaches to modeling PD. Using knockdown and targeted expression systems, we identified a set of mitochondrial, autophagic and neurite-stabilizing functions downstream of PINK1. Using differentiated neuronal cell lines and primary neurons harvested from control and PINK1 knockout mice, we will now determine mechanisms by which PINK1 protects in toxin and genetic PD models, focusing on: 1) the role of subcellular localization in PINK1 regulation of mitochondrial and neurite stability, 2) the effects of PD-linked mutations on mechanisms that regulate these two facets of PINK1 neuroprotection, and 3) continued characterization of potential PINK1 pathway mediators, using candidate and nonbiased proteomic approaches. Achieving the goals of this project to obtain a better understanding of PINK1 regulation of autophagy and mitochondria will provide insight into new therapeutic strategies to reduce neuronal dysfunction in PD.
描述(由申请方提供):PTEN诱导的激酶1(PINK1)突变与常染色体隐性帕金森综合征相关。早期的研究一致表明PINK1具有神经保护作用,这表明研究这种家族性帕金森病(PD)可能为潜在的治疗策略提供有价值的见解。线粒体和自噬的调节异常分别与建模PD的毒素、遗传和环境方法密切相关。使用敲除和靶向表达系统,我们确定了一组线粒体,自噬和神经突稳定功能下游的PINK1。使用从对照和PINK1敲除小鼠中收获的分化的神经元细胞系和原代神经元,我们现在将确定PINK1在毒素和遗传PD模型中的保护机制,重点是:1)亚细胞定位在PINK1调节线粒体和神经突稳定性中的作用,2)PD连锁突变对调节PINK1神经保护的这两个方面的机制的影响,和3)继续表征潜在的PINK1通路介质,使用候选和无偏见的蛋白质组学方法。实现该项目的目标,以更好地了解PINK1对自噬和线粒体的调节,将为减少PD中神经元功能障碍的新治疗策略提供见解。
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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Charleen T Chu其他文献
PSS75 - Functional Roles of Distinct Subcellular Pools of PTEN Induced Kinase-1 on Oxidative Stress and Mitochondrial Function
- DOI:
10.1016/j.freeradbiomed.2013.10.491 - 发表时间:
2013-11-01 - 期刊:
- 影响因子:
- 作者:
Ruben K Dagda;Aaron Gusdon;Charleen T Chu - 通讯作者:
Charleen T Chu
Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy
异丙酚通过 ATG5 和钙依赖性自噬调节影响体外小鼠胚胎成纤维细胞的存活和增殖
- DOI:
10.1038/s41401-019-0303-z - 发表时间:
2019-10 - 期刊:
- 影响因子:8.2
- 作者:
Zhen-dong Xu;Yong Wang;Ge Liang;Zhi-qiang Liu;Wu-hua Ma;Charleen T Chu;Hua-feng Wei - 通讯作者:
Hua-feng Wei
Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy
- DOI:
https://doi.org/10.1038/s41401-019-0303-z - 发表时间:
2019 - 期刊:
- 影响因子:
- 作者:
Zhen-dong Xu;Yong Wang;Ge Liang;Zhi-qiang Liu;Wu-hua Ma;Charleen T Chu;Hua-feng Wei - 通讯作者:
Hua-feng Wei
Charleen T Chu的其他文献
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{{ truncateString('Charleen T Chu', 18)}}的其他基金
Protein homeostasis in a frontotemporal dementia iPSC model
额颞叶痴呆 iPSC 模型中的蛋白质稳态
- 批准号:
10525437 - 财政年份:2022
- 资助金额:
$ 31.98万 - 项目类别:
Dendrite regulation by the mitochondrial kinase PINK1: Implications for PD/LBD
线粒体激酶 PINK1 的树突调节:对 PD/LBD 的影响
- 批准号:
9973247 - 财政年份:2017
- 资助金额:
$ 31.98万 - 项目类别:
Dendrite regulation by the mitochondrial kinase PINK1: Implications for PD/LBD
线粒体激酶 PINK1 的树突调节:对 PD/LBD 的影响
- 批准号:
10199062 - 财政年份:2017
- 资助金额:
$ 31.98万 - 项目类别:
Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death
自噬的调控
- 批准号:
8500862 - 财政年份:2013
- 资助金额:
$ 31.98万 - 项目类别:
Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death
自噬的调控
- 批准号:
8841286 - 财政年份:2013
- 资助金额:
$ 31.98万 - 项目类别:
Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death
自噬的调控
- 批准号:
9269939 - 财政年份:2013
- 资助金额:
$ 31.98万 - 项目类别:
PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
PINK1 对神经元和线粒体稳态的调节
- 批准号:
8269861 - 财政年份:2011
- 资助金额:
$ 31.98万 - 项目类别:
PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
PINK1 对神经元和线粒体稳态的调节
- 批准号:
8697145 - 财政年份:2011
- 资助金额:
$ 31.98万 - 项目类别:
PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
PINK1 对神经元和线粒体稳态的调节
- 批准号:
8181791 - 财政年份:2011
- 资助金额:
$ 31.98万 - 项目类别:
PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
PINK1 对神经元和线粒体稳态的调节
- 批准号:
8089006 - 财政年份:2010
- 资助金额:
$ 31.98万 - 项目类别: