Genetic and environmental modifiers of pathology in amyotrophic lateral sclerosis

肌萎缩侧索硬化症病理学的遗传和环境调节剂

基本信息

项目摘要

Traumatic brain injury (TBI) may be a risk factor for the development of amyotrophic lateral sclerosis (ALS). US military veterans have an increased frequency of ALS, and the veteran population has higher head injury prevalence than the comparable civilian population. Repetitive head impacts (RHI) are a form of mild TBI that can lead to severe cognitive and behavioral symptoms and the progressive neurodegeneration of chronic traumatic encephalopathy (CTE). We have shown that ALS is a relatively frequent comorbidity in CTE (4) and that CTE occurs in a veteran population with ALS. Furthermore, genomic variation in TMEM106B may play an important role in both ALS and CTE disease progression. We hypothesize that TMEM106B is a modifier of disease presentation and severity in ALS and that TBI and RHI alter the associations of TMEM106B with pathology and clinical outcomes in CTE. Currently, there are no disease modifying treatments for ALS or CTE, and little is known about genetic modifiers of disease phenotype in ALS or CTE. This is largely because there has not been a systematic collection of participants with ALS, CTE, and both (ALS+CTE) until now. Our translational approach is to systematically address neurodegeneration in the world’s largest neuropathologically-confirmed autopsy cohort of ALS and CTE subjects on the DNA, RNA, and protein levels, with the goal of identifying novel genetic risk factors, biomarkers, and mechanisms that can be targeted for drug discovery. We have shown that compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation. Furthermore, we have demonstrated that variation in TMEM106B is associated with microglia activation, tau pathology, and clinical symptoms in CTE. Variation in TMEM106B is also related to altered clinical outcomes in ALS, the development of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), and to progranulin (PRGN) levels and modulation of inflammatory pathways. Microglial activation is an early change in both ALS and CTE and may alter disease progression. Our hypothesis, based on our preliminary data, is that variants of TMEM106B have disease-specific associations with altered cytokines, pathology, and clinical disease progression in ALS and CTE. We further hypothesize that TMEM106B variation is associated with altered gene expression networks related to inflammatory pathways that predispose to worse pathological and clinical outcomes in ALS, CTE, and ALS+CTE. Our long-term goal is to uncover genetic and molecular mechanisms underlying the development of ALS and CTE in the setting of TBI. The immediate goal of this research project is to test the hypothesis that the TMEM106B risk allele leads to altered inflammatory gene expression and to determine TMEM106B-related disease modifying gene networks and neuroinflammatory markers that may serve as biomarkers to identify those individuals at risk for developing ALS and CTE and to uncover mechanisms that may be targeted for therapy. Overall, we aim to link a history of TBI to genetic, gene expression, and protein variation in human subjects with a definitive pathological diagnosis of ALS, CTE, and ALS+CTE.
创伤性脑损伤(TBI)可能是肌萎缩侧索硬化(ALS)发生的危险因素。美国 退伍军人肌萎缩侧索硬化症的发生率增加,且退伍军人人群的头部损伤率更高 流行率高于可比的平民人口。重复性头部撞击(RHI)是一种轻度TBI, 可导致严重的认知和行为症状以及慢性 创伤性脑病(CTE)。我们已经证明ALS是CTE中相对常见的合并症(4),并且 CTE发生在患有ALS的退伍军人群体中。此外,TMEM 106 B的基因组变异可能在肿瘤的发生发展中起重要作用。 在ALS和CTE疾病进展中起重要作用。我们假设TMEM 106 B是 ALS和TBI及RHI中疾病表现和严重程度改变了TMEM 106 B与ALS和TBI相关性。 CTE的病理学和临床结局。目前,还没有针对ALS或CTE的疾病改善治疗, 并且对ALS或CTE中疾病表型的遗传修饰物知之甚少。这在很大程度上是因为 迄今为止,尚未系统收集ALS、CTE和两者(ALS+CTE)患者。我们 翻译方法是系统地解决世界上最大的神经退行性变 经神经病理学证实的ALS和CTE受试者尸检队列的DNA、RNA和蛋白质水平, 目的是鉴定新的遗传风险因子、生物标志物和机制, 药物发现。我们已经证明,与单独ALS相比,ALS+CTE共病与 TBI病史并具有独特的临床和病理表现。此外,我们还证明了 TMEM 106 B的变异与小胶质细胞活化、tau病理学和临床症状有关。 热膨胀系数。TMEM 106 B的变异也与ALS的临床结局改变、 额颞叶变性伴TDP-43包涵体(FTLD-TDP),以及颗粒蛋白前体(PRGN)水平和 炎症途径的调节。小胶质细胞活化是ALS和CTE的早期变化,可能 改变疾病进展。基于我们的初步数据,我们的假设是TMEM 106 B的变体 ALS患者中细胞因子改变、病理学和临床疾病进展与疾病特异性相关性,以及 热膨胀系数。我们进一步假设,TMEM 106 B变异与改变基因表达网络有关 与易导致ALS、CTE、 和ALS+CTE。我们的长期目标是揭示基因和分子机制, 在TBI背景下ALS和CTE的发展。本研究项目的近期目标是测试 假设TMEM 106 B风险等位基因导致炎症基因表达改变,并确定 TMEM 106 B相关的疾病修饰基因网络和神经炎性标记物可作为 生物标志物来鉴定那些有发生ALS和CTE风险的个体,并揭示 可以作为治疗的靶点。总之,我们的目标是将创伤性脑损伤的历史与遗传、基因表达和蛋白质联系起来 具有ALS、CTE和ALS+CTE明确病理学诊断的人类受试者中的变异。

项目成果

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Thor Stein其他文献

Thor Stein的其他文献

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{{ truncateString('Thor Stein', 18)}}的其他基金

Cerebrovascular Remodeling and Neurodegenerative Changes in Alzheimer's Disease
阿尔茨海默病的脑血管重塑和神经退行性改变
  • 批准号:
    10554367
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Cerebrovascular Remodeling and Neurodegenerative Changes in Alzheimer's Disease
阿尔茨海默病的脑血管重塑和神经退行性改变
  • 批准号:
    10370614
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease
经典补体途径在神经胶质表型和多种病理学中在阿尔茨海默病和脑血管疾病中的作用
  • 批准号:
    10256776
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease
经典补体途径在神经胶质表型和多种病理学中在阿尔茨海默病和脑血管疾病中的作用
  • 批准号:
    10468286
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease
经典补体途径在神经胶质表型和多种病理学中在阿尔茨海默病和脑血管疾病中的作用
  • 批准号:
    10670360
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease
经典补体途径在神经胶质表型和多种病理学中在阿尔茨海默病和脑血管疾病中的作用
  • 批准号:
    10047360
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
TBI-related polyproteinopathy and the role of multiple neurodegenerations in cognitive decline and parkinsonism
TBI 相关的多蛋白病以及多种神经变性在认知能力下降和帕金森病中的作用
  • 批准号:
    10227045
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
TBI-related polyproteinopathy and the role of multiple neurodegenerations in cognitive decline and parkinsonism
TBI 相关的多蛋白病以及多种神经变性在认知能力下降和帕金森病中的作用
  • 批准号:
    10021469
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
TBI-related polyproteinopathy and the role of multiple neurodegenerations in cognitive decline and parkinsonism
TBI 相关的多蛋白病以及多种神经变性在认知能力下降和帕金森病中的作用
  • 批准号:
    10460268
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
The neuropathology of mild traumatic brain injury in Alzheimer disease
阿尔茨海默病轻度创伤性脑损伤的神经病理学
  • 批准号:
    10294950
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:

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