The role of mitochondrial fission in neurodegeneration in the leading environmental cause of Alzheimer's disease

线粒体裂变在神经变性中的作用是阿尔茨海默病的主要环境原因

• 批准号: 10536447
• 负责人: Preethy Sridharan
• 金额: $ 5.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-08 至 2026-08-07
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536447
• 关键词: Acceleration; Acute; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animals; Axon; Behavioral; Biochemical; Bioenergetics; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Concussion; Brain region; Chronic; Clinical; Cognitive deficits; Collaborations; Confocal Microscopy; Congo Red; Craniocerebral Trauma; Data; Deposition; Deterioration; Development; Disease; Dynamin; Early treatment; Electron Microscopy; Environmental Risk Factor; Equilibrium; Fostering; Functional disorder; Genus Hippocampus; Goals; Hippocampus (Brain); Histologic; Huntington Disease; Immunohistochemistry; Incidence; Injury; Investigation; Link; Measures; Mediating; Mediator of activation protein; Methods; Mitochondria; Modeling; Modification; Monitor; Mus; Nature; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathology; Peptides; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physicians; Play; Post-Translational Protein Processing; Process; Proteins; Regulation; Reporting; Research Personnel; Risk; Role; Scientist; Senile Plaques; Societies; Stains; Symptoms; System; TBI treatment; Techniques; Testing; Time; Training; Transmission Electron Microscopy; Traumatic Brain Injury; axonal degeneration; base; behavior test; career; efficacy study; genetic regulatory protein; inhibitor; injured; insight; mild traumatic brain injury; mitochondrial dysfunction; motor deficit; mouse model; multimodality; neurogenesis; neuroinflammation; neuropsychiatry; novel; object recognition; prevent; recruit; skills

Project Summary/Abstract In the past decade, traumatic brain injury (TBI) has been rising in incidence, and is linked to a 2-4 fold increase in developing Alzheimer's disease and related dementias later in life1–5. TBI presents as a progressive neurodegenerative injury characterized by cognitive deficits and neuropsychiatric impairment4,6. Currently, there are no available treatments to prevent, slow, or reverse the chronic progression of neurodegeneration and accelerated AD after TBI. In many neurodegenerative conditions, including AD, Parkinson's disease, Huntington's disease, aberrant mitochondrial fission has been identified as a critical component of pathogenesis7. It has also been implicated in the acute stages of concussive TBI8–10. The goals of this project are to characterize the changes in regulation of mitochondrial fission that occur in acute and chronic TBI, and to determine whether pharmacologically limiting aberrantly high mitochondrial fission after TBI provides a neuroprotective strategy for TBI and TBI-induced accelerated AD. To address my goal, I propose the following aims, using an established mouse model of TBI: 1. Determine how TBI affects expression, modification, and activity of the key mediator of mitochondrial fission, dynamin-related protein 1 (Drp1). I will measure expression of Drp1 across a comprehensive list of brain regions at early and late timepoints after TBI. I will also measure post-translational modifications, oligomerization activity, and expression of regulatory proteins of Drp1. 2. Determine how pharmacologic inhibition of mitochondrial fission after acute TBI mitigates pathology and symptoms at acute and chronic timepoints after TBI. I will administer injured mice with P110, a small peptide inhibitor of the key mitochondrial fission protein Drp1 which has already been determined to be neuroprotective in TBI, and then investigate pathological changes across an array of histological measures, ultrastructural changes via transmission electron microscopy, and bioenergetic changes via Seahorse analysis. 3. Determine the efficacy of P110 treatment in mitigating TBI-induced acceleration of Alzheimer's disease. I will administer P110 to 5xFAD mice following mild TBI, and use behavioral testing to determine P110's efficacy in reducing accelerated neurocognitive deficits. I will also use histological methods to monitor changes in plaque deposition as a function of TBI and P110 treatment. Through completing this project, I will acquire new lab techniques, including behavioral testing, immunohistochemistry, biochemical assays, and both confocal and electron microscopy. I will also foster collaboration with researchers in related fields of neurodegeneration, and develop clinical insight into the field of neurodegeneration. This proposal outlines a rigorous training plan by which I will establish the skills needed for a successful career as a physician-scientist in the fields of neurodegeneration and neuropsychiatry.

项目摘要/摘要 在过去的十年中，创伤性脑损伤（TBI）的发病率一直在上升，与2-4倍有关 生命后期晚些时候发展阿尔茨海默氏病和相关痴呆症的增加。 TBI表现为进步 以认知缺陷和神经精神障碍为特征的神经退行性损伤4,6。现在， 没有可用的治疗方法可以预防，缓慢或扭转神经退行性的慢性进展和 TBI后加速广告。在许多神经退行性疾病中，包括AD，帕金森氏病， 亨廷顿病，异常线粒体裂变已被确定为 发病机理7。在脑震荡TBI8-10的急性阶段也暗示了它。这个项目的目标是 为了表征急性和慢性TBI的线粒体裂变调节的变化，以及 确定在TBI后，药理学上是否限制了异常高的线粒体裂变 TBI和TBI诱导的加速AD的神经保护策略。 为了解决我的目标，我使用既定的TBI鼠标模型提出以下目标： 1。确定TBI如何影响线粒体关键介体的表达，修饰和活动 裂变，与动力蛋白相关的蛋白1（DRP1）。我将在综合列表中衡量DRP1的表达 在TBI之后的早期和晚期的大脑区域。我还将测量翻译后 DRP1的调节蛋白的修饰，寡聚活性和表达。 2。确定急性TBI后线粒体裂变的药物结肠抑制如何减轻病理 和TBI之后的急性和慢性时点处的符号。我将用P110，A 关键线粒体裂变蛋白DRP1的小胡椒抑制剂 确定在TBI中具有神经保护作用，然后研究跨一系列的病理变化 组织学测量，通过透射电子显微镜的超微结构变化和生物能 通过海马分析变化。 3。确定p110治疗在减轻TBI诱导的阿尔茨海默氏病加速的效率。 在轻度TBI之后，我将管理P110至5XFAD小鼠，并使用行为测试来确定 P110在减少加速神经认知缺陷方面有效。我还将使用组织学方法 监测斑块沉积的变化是TBI和P110处理的函数。 通过完成该项目，我将获得新的实验室技术，包括行为测试， 我还将促进生化测定以及共聚焦和电子显微镜。 与神经变性领域的研究人员合作，并发展对该领域的临床见解 神经变性。该建议概述了一个严格的培训计划，我将确定所需的技能 在神经退行性和神经精神病学领域的身体科学家的成功职业生涯。