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

项目总结/摘要 创伤性脑损伤（TBI）引发原发性和继发性损伤， 显著增加神经退行性疾病的发展风险， 额颞叶痴呆（FTLD）和运动神经元疾病，如肌萎缩侧索硬化症 （ALS）。目前，对于TBI或相关的神经退行性疾病没有标准的治疗或治愈方法。 对症治疗和支持治疗以外的疾病。该项目的目标是 评估和分类FTLD和ALS样神经退行性影响皮质的程度， TBI后的运动神经元、后脑运动神经元和前运动神经元以及脊髓运动神经元。的 该项目的总体目标有两个：首先，提供FTLD和ALS的彻底分析， 像长期的神经退行性影响，这将有助于减轻知识差距与具体的 关于TBI后神经退行性病变的细胞信息;其次， 为更广泛的治疗研究奠定了可行性研究的基础， 最大限度地降低日后发生TBI相关神经退行性疾病的固有风险。的 这项研究的具体目的是确定继发性神经退行性病变的影响， TBI动物模型中的损伤。这些影响包括细胞表型的变化， 通过来自免疫组织化学（IHC）和RNA-seq分析的数据测量的功能。 IHC分析将重点关注已知的和临床相关的FTLD和ALS样特异性标志物 神经变性，包括蛋白质易位和聚集在目标地区（额叶 皮质、后脑、颈脊髓）。将对同侧和对侧进行RNA-seq分析。 额叶皮层和颈脊髓的区域。将进行分析，以检测差异 表达的基因和选择性剪接转录之间的损伤和未损伤的半球， 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 从这些特定目标中获得的信息将用于设计预防性治疗，以减轻 在创伤性脑损伤后发展成神经退行性疾病

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.