Linking TBI secondary injuries to FTLD- and ALS-like neurodegeneration

TBI 继发性损伤与 FTLD 和 ALS 样神经变性的联系

基本信息

批准号：
10309060
负责人：
ROBERT P BOWSER
金额：
$ 15.7万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10309060
关键词：
Address Alternative Splicing Amyotrophic Lateral Sclerosis Animal Model Animals Appearance Area Biological Markers Brain Injuries Brain Stem Catalogs Cell Nucleus Cervical spinal cord structure Cessation of life Chronic Contralateral Control Animal Cytoplasm Data Development Early Intervention Emergency Situation Emergency department visit Feasibility Studies Frontotemporal Dementia Future Genetic Predisposition to Disease Genetic Transcription Goals Head Hospitalization Human Injury Investigation Ipsilateral Knowledge Lead Life Link Measures Messenger RNA Methodology Military Personnel Mission Molecular Motor Motor Cortex Motor Neuron Disease Motor Neurons Nerve Degeneration Nervous System Trauma Neurobiology Neurodegenerative Disorders Neurons Pathologic Pathology Phenotype Planning Techniques Preventive therapy Process Prosencephalon Protein translocation Public Health Reporting Research Risk Spinal Cord Spinal cord grey matter structure Spliced Genes Sports Supportive care Therapeutic Therapeutic Intervention Tissues Transcript Traumatic Brain Injury Ubiquitination United States United States National Institutes of Health Variant cell injury clinically relevant cognitive disability controlled cortical impact design differential expression frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis functional disability hindbrain injured motor disorder mouse model nervous system disorder novel novel therapeutics pre-clinical protein TDP-43 protein aggregation standard care symptom treatment targeted treatment therapeutic development therapy design transcriptome sequencing transcriptomics wound

项目摘要

Project Summary/Abstract Traumatic brain injury (TBI) initiates primary and secondary damage that may lead to a significantly increased risk for the development of neurodegenerative disorders such as frontotemporal lobar dementia (FTLD) and motor neuron diseases like amyotrophic lateral sclerosis (ALS). Currently there are no standard treatments or cures for TBIs or associated neurodegenerative disorders other than symptomatic treatment and supportive therapies. The goal of this project is to assess and catalogue the extent of FTLD- and ALS-like neurodegenerative effects on cortical neurons, hindbrain motor and premotor neurons, and spinal cord motor neurons following a TBI. The overall objective of this project is twofold: first, to provide a thorough analysis of the FTLD- and ALS- like long-term neurodegenerative effects that will help to alleviate a knowledge gap with specific cellular information concerning the neurodegenerative pathologies following a TBI; and secondly, as the basis of a feasibility study for a much broader investigation into treatment therapies designed to minimize the inherent risk of developing TBI-related neurodegenerative disease later in life. The specific aims of this study are designed to determine the neurodegenerative effects of secondary injuries in an animal model of TBI. These effects include the changes in cellular phenotypes and functions as measured through data derived from immunohistochemical (IHC) and RNA-seq analysis. IHC analysis will focus on known and clinically relevant specific markers of FTLD- and ALS-like neurodegeneration including protein translocations and aggregations in the targeted areas (frontal cortex, hindbrain, cervical spinal cord). RNA-seq analysis will be performed on ipsi- and contralateral areas of the frontal cortex and cervical spinal cord. Analysis will be performed to detect differentially expressed genes and alternative spliced transcripts between injured and uninjured hemispheres of a TBI animal model to tissue collected from uninjured control animals. The data and knowledge obtained from these specific aims will be used to design preventative therapies to alleviate the risk of developing future neurodegenerative disease following TBI.

项目摘要/摘要创伤性脑损伤（TBI）启动了一级和继发损伤，可能导致明显增加了神经退行性疾病的发展的风险，例如额颞叶痴呆症（FTLD）和运动神经元疾病，如肌萎缩性侧索硬化症（ALS）。目前尚无针对TBI或相关神经退行性的标准治疗方法除症状治疗和支持疗法以外的其他疾病。这个项目的目标是评估和分类FTLD和ALS样神经退行性对皮质的影响的程度 TBI后，神经元，后脑运动和前神经元以及脊髓运动神经元。这该项目的总体目标是双重的：首先，对FTLD和ALS-进行彻底分析就像长期神经退行性效应一样，将有助于减轻特定的知识差距 TBI后有关神经退行性病理的细胞信息；其次，如可行性研究的基础，用于对旨在的治疗疗法进行更广泛的研究最大程度地减少生命后期与TBI相关神经退行性疾病的固有风险。这这项研究的具体目的旨在确定次级的神经退行性效应 TBI动物模型中的伤害。这些影响包括细胞表型的变化和通过从免疫组织化学（IHC）和RNA-Seq分析得出的数据来测量的功能。 IHC分析将集中于已知和临床相关的FTLD和ALS样标记神经变性，包括靶向区域的蛋白质易位和聚集皮质，后脑，宫颈脊髓）。 RNA-seq分析将在IPSI和对侧进行额叶皮质和颈椎的区域。将进行分析以差异检测表达的基因和A的替代剪接转录本 TBI动物模型与从未受伤的对照动物收集的组织。数据和知识从这些特定目的获得的将用于设计预防性疗法，以减轻 TBI后发展未来的神经退行性疾病。