Role of phospholipids in regulating neurotoxin induced mitochondrial autophagy

描述（由申请人提供）：失调的自噬与几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调节过程，自噬体将货物递送到溶酶体进行降解。自噬隔离需要自噬机制的组成部分结合到前自噬体膜上。基础自噬对于维持神经元中线粒体的稳态至关重要，无论是受损的还是过量的线粒体！周转可能导致神经变性。然而，调节受损细胞器如线粒体的选择性靶向的机制是未知的。我们最近的研究表明，替代脂质信号参与信号线粒体！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Cardlolipn（CL）通过与自噬机制的相互作用触发线粒体自噬。跨学科的方法，包括质谱，高效薄层色谱，脂质包被的纳米粒子，活细胞成像，和突变分析将被用来测试这一假设，通过两个具体的目标，重点是CL在触发线粒体自噬的作用和机制的相互作用与自噬机制。申请人为博士后研究员，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进行培训。将定期举行涉及申请人，他的跨学科指导团队和外部顾问的会议，以确保分子细胞生物学，生物化学和神经退行性疾病的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，成为神经变性研究的独立研究者。Lay摘要。除了为细胞能量需求提供动力外，线粒体还积极调节神经元的生存/死亡决定。线粒体！这些改变与神经退行性疾病有关， 精神疾病和衰老。因为自噬是线粒体中的关键因素！通过质量控制，拟议研究的科学创新可以通过揭示帕金森病和其他年龄相关神经退行性过程的治疗相关机制而使更大的社区受益。

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.