Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death
Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death
批准号:
8500862
负责人:
Charleen T Chu
金额:
$31.26万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-05-01 至 2018-04-30
关键词:
1-Methyl-4-phenylpyridiniumAnabolismAutophagocytosisBiogenesisCell DeathCellsCessation of lifeChronicComplexDataDefectDoseEmbryoEnergy-Generating ResourcesEquilibriumGenesGenetic ModelsHealthImpairmentIn VitroInjuryLinkMaintenanceMediatingMidbrain structureMitochondriaMitochondrial DNAModelingMusNatural regenerationNerve DegenerationNeuritesNeurodegenerative DisordersNeuronal InjuryNeuronsNeurotoxinsNuclearOrganellesOutcomePPAR gammaParkinson DiseaseParkinsonian DisordersPatientsPhosphorylationPhosphorylation SitePlayProcessProtein BiosynthesisProtein KinaseProteinsRecyclingRegulationResearchRoleSignal TransductionSystemTestingToxic effectToxinTransfectionTranslationsbrain cellcofactorextracellulargenetic regulatory proteinin vivoinhibitor/antagonistleucine-rich repeat kinase 2mitochondrial autophagymitochondrial dysfunctionmouse modelmtTF1 transcription factormutantneuroblastoma cellneuron lossneuroprotectionpublic health relevanceregenerative
中文摘要
描述(由申请人提供):维持功能良好的线粒体在神经元健康中起着关键作用。在之前的项目期间,我们发现在帕金森病神经变性的几种神经毒素和遗传模型中,神经元损伤集中在通过自噬(有丝分裂)导致线粒体周转增加的情况下。虽然有丝分裂吞噬在一些模型中具有神经保护作用,但在另一些模型中,抑制自噬可以减少轴突回缩和细胞死亡。我们假设,在这种情况下,通过线粒体生物发生来替换受损/退化的线粒体的能力在决定生存-死亡结果方面是重要的。初步数据表明,细胞外信号调节蛋白激酶2(ERK2)在调节有丝分裂和线粒体生物发生中起着关键作用。ERK2显示了帕金森病中脑神经元线粒体分布的改变。我们将利用分化的神经母细胞瘤细胞、原代胚胎小鼠神经元和活体小鼠模型来研究(S)导致观察到的线粒体含量和功能下降的机制,研究磷酸化在调节生物发生中的作用,并确定调节毒素和帕金森病显性遗传模型中线粒体含量的策略的神经保护潜力。
英文摘要
DESCRIPTION (provided by applicant): The maintenance of well-functioning mitochondria plays a key role in neuronal health. In the previous project period, we found that neuronal injury in several neurotoxin and genetic models of parkinsonian neurodegeneration converged on eliciting increased mitochondrial turnover by autophagy (mitophagy). While mitophagy in some models is neuroprotective, in other models, inhibiting autophagy reduces neurite retraction and cell death. We hypothesize that the capacity to replace damaged/degraded mitochondria through mitochondrial biogenesis is important in determining survival-death outcomes in this context. Preliminary data indicate a key role for extracellular signal-regulated protein kinase 2 (ERK2), which shows an altered mitochondrial distribution in Parkinson's disease midbrain neurons, in regulating both mitophagy and mitochondrial biogenesis. We will utilize differentiated neuroblastoma cells, primary embryonic mouse neurons and in vivo mouse models to study the mechanism(s) leading to the observed decreases in mitochondrial content and function, study the role of phosphorylation in regulating biogenesis, and determine the neuroprotective potential for strategies to modulate mitochondrial content in toxin and dominant genetic models of Parkinson's disease.
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PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
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PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
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资助金额:$33.14万
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财政年份:2011
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PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
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资助金额:$31.98万
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PINK1 Regulation of Neuronal and Mitochondrial Homeostasis
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Regulation of autophagy in dopaminergic cell death
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Neuronal quality control and neuroprotection in tauopathies
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Regulation of autophagy in dopaminergic cell death
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海外基金