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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要/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 倍相关晚年罹患阿尔茨海默病和相关痴呆症的几率增加1-5。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。没有可用的治疗方法来预防、减缓或逆转神经退行性变的慢性进展 TBI 后加速 AD 在许多神经退行性疾病中，包括 AD、帕金森病、亨廷顿病，异常的线粒体裂变已被确定为亨廷顿病的关键组成部分发病机制7. 它也与脑震荡 TBI8-10 的急性阶段有关。描述急性和慢性 TBI 中发生的线粒体裂变调节的变化，并确定药物限制 TBI 后异常高的线粒体裂变是否提供了 TBI 和 TBI 诱发的加速 AD 的神经保护策略。为了实现我的目标，我使用已建立的 TBI 小鼠模型提出以下目标： 1. 确定 TBI 如何影响线粒体关键介质的表达、修饰和活性裂变、动力相关蛋白 1 (Drp1) 我将在一个综合列表中测量 Drp1 的表达。我还将测量 TBI 后早期和晚期时间点的大脑区域。 Drp1 的修饰、寡聚化活性和调节蛋白的表达。 2. 确定急性 TBI 后线粒体裂变的药物抑制如何减轻病理以及 TBI 后急性和慢性时间点的症状，我会给受伤的小鼠注射 P110，一种关键线粒体裂变蛋白 Drp1 的小肽抑制剂，已被确定对 TBI 具有神经保护作用，然后研究一系列的病理变化组织学测量、通过透射电子显微镜观察超微结构变化以及生物能通过海马分析进行更改。 3. 确定 P110 治疗在减轻 TBI 引起的阿尔茨海默病加速方面的功效。我将在轻度 TBI 后对 5xFAD 小鼠施用 P110，并使用行为测试来确定 P110 在减少加速性神经认知缺陷方面的功效我还将使用组织学方法来研究。监测斑块沉积随 TBI 和 P110 治疗的变化。通过完成这个项目，我将获得新的实验室技术，包括行为测试，我还将培养免疫组织化学、生化测定以及共聚焦和电子显微镜。与神经退行性疾病相关领域的研究人员合作，并发展对该领域的临床洞察力该提案概述了一个严格的培训计划，我将通过该计划建立所需的技能。作为一名在神经退行性疾病和神经精神病学领域取得成功的医师科学家。