Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death

自噬的调控

• 批准号: 9269939
• 负责人: Charleen T Chu
• 金额: $ 31.57万
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269939
• 关键词: 1-Methyl-4-phenylpyridinium; Anabolism; Autophagocytosis; Autopsy; Biogenesis; Cell Death; Cells; Cessation of life; Chronic; Complex; Data; Defect; Dominant Genetic Conditions; Dose; Embryo; Energy-Generating Resources; Equilibrium; Genes; Genetic Models; Genetic Transcription; Health; Impairment; In Vitro; Injury; LRRK2 gene; Link; Maintenance; Mediating; Midbrain structure; Mitochondria; Mitochondrial DNA; Modeling; Morphology; 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; factor A; genetic regulatory protein; in vivo; inhibitor/antagonist; mitochondrial autophagy; mitochondrial dysfunction; mouse model; mtTF1 transcription factor; mutant; neuroblastoma cell; neuron loss; neuroprotection; public health relevance; regenerative; survival outcome; transcription factor

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起关键作用。在上一个项目时期，我们发现帕金森神经退行性的几种神经毒素和遗传模型中的神经元损伤会伴随着自噬（mitophagy）提高线粒体更新的增加。尽管某些模型中的线粒体具有神经保护作用，但在其他模型中，抑制自噬可减少神经突收缩和细胞死亡。我们假设在这种情况下，通过线粒体生物发生替代线粒体生物发生的损坏/退化的线粒体的能力很重要。初步数据表明，细胞外信号调节的蛋白激酶2（ERK2）的关键作用，该蛋白质激酶2（ERK2）在调节线粒体和线粒体生物发生方面显示了帕金森氏病中脑神经元中线粒体分布的改变。 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.