Neuronal exosomes to identify biomarkers and pathology of deployment-related TBI

神经元外泌体识别部署相关 TBI 的生物标志物和病理学

• 批准号: 10046280
• 负责人: Victoria B Risbrough
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046280
• 关键词: Acute; Address; Affect; Afghanistan; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Behavioral; Biological Markers; Blood; Blood specimen; Brain Injuries; Caliber; Calpain; Cells; Chronic; Cleaved cell; Clinical Trials; Cognitive; Companions; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Endosomes; Enrollment; Evaluation; Exhibits; Future; Genes; Genetic; Human; Image; Impaired cognition; Individual; Inflammatory; Injury; Intervention; Length; Life; Light; Link; Liquid substance; Longitudinal prospective study; Marines; Measures; Membrane; Mental Health; Messenger RNA; MicroRNAs; Molecular; N-terminal; Nerve Degeneration; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurofilament-L; Neurologic; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropsychology; Participant; Pathogenicity; Pathology; Pathway interactions; Patients; Performance; Phase; Plasma; Population Attributable Risks; Post-Concussion Syndrome; Process; Prognosis; Proteins; Publishing; RNA; Recording of previous events; Regulation; Reporting; Risk; Risk Factors; Sampling; Severities; Small RNA; Source; Specificity; Spectrin; Symptoms; Synapses; Testing; Tissues; Traumatic Brain Injury; Unconscious State; Vesicle; Veterans; Work; active duty; associated symptom; base; biomarker validation; cell type; cognitive performance; cohort; combat; combat training; comorbidity; cost; exosome; experience; functional decline; functional disability; genome-wide; mild cognitive impairment; mild traumatic brain injury; neurofilament; neurogranin; neuropathology; novel; peripheral blood; persistent symptom; physical conditioning; potential biomarker; prospective; protein biomarkers; protein expression; resilience; sample collection; service member; specific biomarkers; targeted treatment; tau Proteins; tau-1; therapeutic target; tool; transcriptome sequencing; treatment strategy; vesicular release; Acute; Address; Affect; Afghanistan; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Behavioral; Biological Markers; Blood; Blood specimen; Brain Injuries; Caliber; Calpain; Cells; Chronic; Cleaved cell; Clinical Trials; Cognitive; Companions; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Endosomes; Enrollment; Evaluation; Exhibits; Future; Genes; Genetic; Human; Image; Impaired cognition; Individual; Inflammatory; Injury; Intervention; Length; Life; Light; Link; Liquid substance; Longitudinal prospective study; Marines; Measures; Membrane; Mental Health; Messenger RNA; MicroRNAs; Molecular; N-terminal; Nerve Degeneration; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurofilament-L; Neurologic; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropsychology; Participant; Pathogenicity; Pathology; Pathway interactions; Patients; Performance; Phase; Plasma; Population Attributable Risks; Post-Concussion Syndrome; Process; Prognosis; Proteins; Publishing; RNA; Recording of previous events; Regulation; Reporting; Risk; Risk Factors; Sampling; Severities; Small RNA; Source; Specificity; Spectrin; Symptoms; Synapses; Testing; Tissues; Traumatic Brain Injury; Unconscious State; Vesicle; Veterans; Work; active duty; associated symptom; base; biomarker validation; cell type; cognitive performance; cohort; combat; combat training; comorbidity; cost; exosome; experience; functional decline; functional disability; genome-wide; mild cognitive impairment; mild traumatic brain injury; neurofilament; neurogranin; neuropathology; novel; peripheral blood; persistent symptom; physical conditioning; potential biomarker; prospective; protein biomarkers; protein expression; resilience; sample collection; service member; specific biomarkers; targeted treatment; tau Proteins; tau-1; therapeutic target; tool; transcriptome sequencing; treatment strategy; vesicular release

Traumatic brain injury (TBI) is a signature injury of OIF/OEF Veterans. More than 360,000 armed service members sustained TBI during combat and training from 2000 to 2016. There is currently no diagnostic biological marker for TBI nor can current diagnostic tools identify individuals at greatest risk for chronic neurological and subsequent functional impairments after TBI. Neuronally-derived exosomes (NDEs) obtained from peripheral blood may be a powerful tool to develop accessible CNS-based biomarkers associated with neuronal dysfunction, particularly in relation to long-term brain injury and neurodegeneration. Our recently published work demonstrates that neuropathological proteins (e.g betaamyloid, Aß, and tau) within NDEs can predict conversion from mild cognitive impairment to Alzheimer's Disease (AD) while plasma levels do not. Studies of NDEs are now being tested as companion biomarkers in AD clinical trials to help reduce screen fail rates and increased enrollment. We have recently found that cytoskeletal and synaptic proteins are also abnormal in deployment-related TBI patients >3 mo after TBI. Specifically, both Aß and neurogranin are altered in plasma NDEs from participants who experienced a deployment-related TBI. Taken together, our data support the hypothesis that plasma NDEs may be a powerful tool to identify accessible and CNS-specific protein biomarkers for TBI. NDEs are also enriched for short length “micro” RNA (miRNA) cargo. Each miRNA can regulate protein expression from hundreds of target messenger RNAs, providing an efficient mechanism to exert genome-wide regulation and simultaneously affect several cellular pathways. miRNAs confer tissue specificity and have recently emerged as potential biomarkers and therapeutic targets for neurodegeneration. Hence, identification of CNS-specific miRNAs associated with NDEs may provide a window to the pathogenic processes in chronic TBI for future intervention. We hypothesize that proteins related to neurodegeneration within NDEs, such as Aß, as well as miRNAs associated with NDEs have the potential to be biomarkers of TBI and associated symptoms. To test this hypothesis we will leverage our prospective longitudinal study of combat deployment effects in >1200 Marines, of which 176 experienced mild/moderate deployment-related TBI. This study collected physical and mental health, neurocognitive performance and blood samples 1 mo before and 4-6 mo after a combat deployment to Afghanistan. We will use 150 TBI samples with 150 samples of matched controls with no TBI history to complete 2 aims. Aim 1 will examine utility of cytoskeletal and neuronal proteins in NDEs to identify TBI in addition to persistence of post-concussive symptoms and cognitive decline. Candidate neurodegenerative proteins include tau, Aß, neurogranin, neurofilament light chain and calpain-cleaved αII-spectrin N-terminal fragment. Studies will also leverage these prospective samples to examine if change in NDE proteins from pre-and post injury reflects symptom change, providing potential causal inferences for these proteins in the pathogenic process of TBI. Aim 2 will use an unbiased discovery approach to identify novel miRNAs associated with TBI and associated symptoms and neurocognitive decline. Small RNA sequencing will be conducted on exosomal RNA. miRNA associated with TBI will be validated using RT-qPCR and replicated in an independent sample set. Top candidates will be examined for changes pre and post injury to understand the contribution of these markers to the pathogenic process after injury. This study has strong potential to provide accessible, quantitative biomarkers for TBI and associated symptoms, as well as identify potential functional targets for intervention. ! !

创伤性脑损伤（TBI）是OIF/OEF退伍军人的标志性损伤。超过360,000名武装服务 成员在2000年至2016年的战斗和培训期间维持TBI。目前尚无诊断 TBI的生物标记物也无法确定慢性风险最大的个体 TBI后神经系统和随后的功能障碍。神经源性外泌体（NDES） 从外周血获得的可能是开发基于CNS的生物标志物的强大工具 与神经元功能障碍有关，特别是与长期脑损伤和 神经变性。我们最近发表的工作表明神经病理学蛋白（例如 NDE中的βAmyboid，Aß和Tau）可以预测从轻度认知障碍到 阿尔茨海默氏病（AD），而血浆水平则没有。 NDE的研究现在正在作为同伴测试 AD临床试验中的生物标志物有助于降低筛查失败率和增加入学率。我们最近有 发现细胞骨架和突触蛋白在部署相关的TBI患者中也异常 在TBI之后。具体而言，在参与者的血浆NDE中，Aß和神经素蛋白都会改变 经历了与部署相关的TBI。综上所述，我们的数据支持等离子体NDE的假设 可能是识别TBI的可访问和CNS特异性蛋白质生物标志物的强大工具。 NDE也是 富含短长度“微型” RNA（miRNA）货物。每个miRNA可以从 数百个目标使者RNA，提供有效的机制来发挥全基因组调节 只是影响几种细胞途径。 miRNA会议组织特异性，最近 成为神经退行性的潜在生物标志物和治疗靶标。因此，识别 与NDE相关的中枢神经系统特异性miRNA可能为慢性致病过程提供一个窗口 TBI以后进行干预。我们假设蛋白质与NDE中的神经退行性相关， 例如Aß，以及与NDE相关的miRNA都有可能成为TBI的生物标志物和 相关符号。为了检验这一假设，我们将利用我们的前瞻性纵向研究 战斗部署效果> 1200海军陆战队，其中176次经历了与部署有关的轻度/中等部署 TBI。这项研究收集了身心健康，神经认知表现和血液样本1 mo 在战斗部署到阿富汗之后，在4-6个月之前。我们将使用150个TBI样品150 没有TBI历史记录的匹配控件样本可以完成2个目标。 AIM 1将检查 NDES中的细胞骨架和神经元蛋白，除了持续的持续性外，还可以识别TBI 症状和认知能力下降。候选神经退行性蛋白包括tau，aß，神经素蛋白， 神经丝轻链和钙蛋白酶旋转的αII-spectrin n末端片段。研究也将利用 这些前瞻性样本以检查损伤前后NDE蛋白的变化是否反映了症状 变化，在TBI的致病过程中为这些蛋白质提供了潜在的因果推断。 AIM 2意志 使用公正的发现方法来识别与TBI和相关相关的新型miRNA 症状和神经认知能力下降。小的RNA测序将在外泌体RNA上进行。 与TBI相关的miRNA将使用RT-QPCR验证并在独立的样本集中复制。 最高候选人将在受伤前后检查以了解这些贡献 受伤后致病过程的标记。这项研究具有可访问的强大潜力， TBI和相关符号的定量生物标志物，并确定潜在的功能目标 干涉。呢 呢