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.

项目总结/文摘