Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death

自噬的调控

• 批准号: 8841286
• 负责人: Charleen T Chu
• 金额: $ 30.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841286
• 关键词: 1-Methyl-4-phenylpyridinium; Anabolism; Autophagocytosis; Biogenesis; Cell Death; Cells; Cessation of life; Chronic; Complex; Data; Defect; Dose; Embryo; Energy-Generating Resources; Equilibrium; Genes; Genetic Models; Health; Impairment; In Vitro; Injury; Link; Maintenance; Mediating; Midbrain structure; Mitochondria; Mitochondrial DNA; Modeling; Mus; Natural regeneration; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neurotoxins; Nuclear; Organelles; Outcome; PPAR gamma; Parkinson Disease; Parkinsonian Disorders; Patients; Phosphorylation; Phosphorylation Site; Play; Process; Protein Biosynthesis; Protein Kinase; Proteins; Recycling; Regulation; Research; Role; Signal Transduction; System; Testing; Toxic effect; Toxin; Transfection; Translations; brain cell; cofactor; extracellular; genetic regulatory protein; in vivo; inhibitor/antagonist; leucine-rich repeat kinase 2; mitochondrial autophagy; mitochondrial dysfunction; mouse model; mtTF1 transcription factor; mutant; neuroblastoma cell; neuron loss; neuroprotection; regenerative

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.

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发挥着关键作用。在之前的项目期间，我们发现几种神经毒素和帕金森神经变性遗传模型中的神经元损伤集中在通过自噬（线粒体自噬）引起线粒体周转增加。虽然线粒体自噬在某些模型中具有神经保护作用，但在其他模型中，抑制自噬可减少神经突回缩和细胞死亡。我们假设通过线粒体生物发生替换受损/降解的线粒体的能力对于确定这种情况下的生存-死亡结果非常重要。初步数据表明细胞外信号调节蛋白激酶 2 (ERK2) 在调节线粒体自噬和线粒体生物合成中发挥着关键作用，该蛋白显示帕金森病中脑神经元中线粒体分布发生改变。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体内小鼠模型来研究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，并确定策略的神经保护潜力调节毒素中的线粒体含量和帕金森病的显性遗传模型。