Role of phospholipids in regulating neurotoxin induced mitochondrial autophagy

磷脂在调节神经毒素诱导的线粒体自噬中的作用

基本信息

批准号：
7333576
负责人：
RUBEN K DAGDA
金额：
$ 5.81万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7333576
关键词：
1-Methyl-4-phenylpyridinium Affect Age Autophagocytosis Autophagolysosome Autophagosome Binding Biochemical Biological Assay Carbon Nanotubes Cardiolipins Cell Death Cells Cellular biology Cessation of life Charge Class Commit Communities Computational Biology Confocal Microscopy Data Deletion Mutagenesis Development Dose Electrophoresis Ensure Experimental Models Helix (Snails)High Pressure Liquid Chromatography Homeostasis Human Imaging Techniques In Vitro Injury Kinetics Lead Lecithin Life Lipids Liposomes Lysosomes Mass Spectrum Analysis Mediating Membrane Mental disorders Mentors Mentorship Mitochondria Modeling Molecular N-terminal Nanotechnology Nanotubes Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Neuropharmacology Neurotoxins Organelles Outer Mitochondrial Membrane Oxidative Stress Oxidopamine Parkinson Disease Parkinsonian Disorders Performance Phosphatidylinositols Phospholipids Postdoctoral Fellow Process Protein Overexpression Proteins Quality Control Rate Recombinants Regulation Research Research Personnel Research Training Role Rotenone Ruthenium Ben Signal Transduction Staining method Stains Starvation Stimulus Suspension substance Suspensions System Testing Therapeutic Intervention Thin Layer Chromatography Toxin Training Western Blotting age related career cellular imaging ear helix experience in vivo injured innovation interdisciplinary approach mitochondrial autophagy multidisciplinary mutant nanoparticle neuronal survival novel therapeutics oxidation receptor skills

项目摘要

DESCRIPTION (provided by applicant): Dysregulated autophagy has been implicated in several human neurodegenerative diseases and their models. Macroautophagy is a regulated process for engulfment of cytoplasmic constituents into organelles termed autophagosomes, which deliver the cargo to lysosomes for degradation. Autophagic sequestration requires conjugation of components of the autophagy machinery to the pre-autophagosome membrane.Basal autophagy is critical for maintaining mitochondria) homeostasis in neurons, and either impaired or excessive mitochondria! turnover may contribute to neurodegeneration. However, mechanisms that regulate selective targeting of damaged organelles such as mitochondria are unknown. Our recent study indicates that alternative lipid signals are involved in signaling mitochondria! Autophagy during parkinsonian injury, and these signals are distinct from the commonly studied lipid signals that regulate nonselective starvation-induced autophagy. We hypothesize that oxidation and exposure of the mitochondria! inner membrane phospholipid cardlolipln (CL) triggers mitophagy through interactions with the autophagy machinery. Interdisciplinary approaches including mass spectrometry, high performance thin layer chromatography, lipid coated nanoparticles, live cell imaging, and mutational analysis will be employed to test this hypothesis through two specific aims that focus on the role of CL in triggering mitophagy and the mechanism of interaction with the autophagy machinery. The applicant is a postdoctoral fellow with experience in molecular neuropharmacology. To conduct the proposed studies, he will train under the multidisciplinary mentorship of experts in autophagic cell biology and Parkinson's disease mechanisms, oxidative lipidomics and nanotechnology, computational biology and specialized biologic imaging techniques. Regular meetings involving the applicant, his interdisciplinary mentoring team, and external advisors will be held to ensure effective integration of molecular cell biologic, biochemical and neurodegenerative considerations. The two-year research training plan will enable the applicant to derive career developmental skills to become an independent investigator in neurodegeneration research. Lay Summary. In addition to powering cellular energy needs, mitochondria actively regulate neuronal survival/death decisions. Mitochondria! alterations are implicated in neurodegenerative and psychiatric diseases and in aging. As autophagy is a key factor in mitochondria! quality control, scientific innovations from the proposed research can benefit the larger community by unveiling therapeutically relevant mechanisms in Parkinson's and other age-related neurodegenerative processes.

描述（由申请人提供）：自噬失调与多种人类神经退行性疾病及其模型有关。巨自噬是一种将细胞质成分吞噬到称为自噬体的细胞器中的受调节过程，该细胞器将货物运送到溶酶体进行降解。自噬隔离需要自噬机制的组件与自噬体前膜缀合。基础自噬对于维持神经元中线粒体的稳态至关重要，无论线粒体受损还是过量！营业额可能会导致神经退行性变。然而，调节选择性靶向受损细胞器（例如线粒体）的机制尚不清楚。我们最近的研究表明，替代脂质信号参与线粒体信号传导！帕金森损伤期间的自噬，这些信号与通常研究的调节非选择性饥饿诱导的自噬的脂质信号不同。我们假设线粒体的氧化和暴露！内膜磷脂 Cardlolipln (CL) 通过与自噬机制相互作用触发线粒体自噬。将采用包括质谱、高性能薄层色谱、脂质包被纳米粒子、活细胞成像和突变分析在内的跨学科方法，通过两个具体目标来检验这一假设，这两个目标重点关注 CL 在触发线粒体自噬中的作用以及与 CL 相互作用的机制。自噬机制。申请人是一名博士后研究员，具有分子神经药理学经验。为了进行拟议的研究，他将在自噬细胞生物学和帕金森病机制、氧化脂质组学和纳米技术、计算生物学和专业生物成像技术专家的多学科指导下接受培训。将定期举行由申请人、其跨学科指导团队和外部顾问参加的会议，以确保分子细胞生物学、生化和神经退行性考虑因素的有效整合。为期两年的研究培训计划将使申请人获得职业发展技能，成为神经退行性疾病研究的独立研究者。平铺总结。除了满足细胞能量需求外，线粒体还积极调节神经元的生存/死亡决策。线粒体！改变与神经退行性病变有关精神疾病和衰老。因为自噬是线粒体的关键因素！质量控制，拟议研究的科学创新可以通过揭示帕金森氏症和其他与年龄相关的神经退行性过程的治疗相关机制，使更大的社区受益。