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: 9561543
• 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/9561543
• 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; Comorbidity; 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; Proteins; Publishing; RNA; Recording of previous events; Regulation; Reporting; Risk; Risk Factors; Sampling; Severities; Small RNA; Source; Specificity; Spectrin; Symptoms; Synapses; Testing; Tissues; Training; Traumatic Brain Injury; Unconscious State; Vesicle; Veterans; Work; associated symptom; base; biomarker validation; cell type; cognitive performance; cohort; combat; cost; exosome; experience; functional decline; functional disability; genome-wide; mild cognitive impairment; mild traumatic brain injury; neurofilament; neurogranin; neuropathology; novel; outcome forecast; peripheral blood; persistent symptom; physical conditioning; potential biomarker; prospective; protein S precursor; 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36万武装人员 2000年至2016年间，有成员在战斗和训练中遭受过TBI。目前尚无诊断依据 目前的诊断工具也无法识别 TBI 的生物标志物，识别慢性病风险最大的个体。 TBI 后神经系统和随后的功能障碍。神经源性外泌体 (NDE) 从外周血中获取可能是开发可利用的基于中枢神经系统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，神经病理蛋白（例如 濒死体验中的β淀粉样蛋白、Aß和tau蛋白）可以预测从轻度认知障碍转变为 阿尔茨海默病 (AD)，而血浆水平则不然。对濒死体验的研究现在正在作为同伴进行测试 AD 临床试验中的生物标志物有助于降低筛查失败率并增加入学率。我们最近有 发现与部署相关的 TBI 患者 >3 个月后，细胞骨架和突触蛋白也异常 TBI 后。具体来说，Aß 和神经粒蛋白在血浆濒死体验中发生了改变，这些参与者 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濒死体验的假设 可能是识别 TBI 的可访问且中枢神经系统特异性蛋白质生物标志物的强大工具。濒死体验也是 富含短长度“微小”RNA (miRNA) 货物。每个 miRNA 都可以调节蛋白质的表达 数百个目标信使RNA，提供了发挥全基因组调控的有效机制 并同时影响多个细胞途径。 miRNA 赋予组织特异性，最近 成为神经退行性疾病的潜在生物标志物和治疗靶点。因此，识别 与濒死体验相关的中枢神经系统特异性 miRNA 可能为慢性病的致病过程提供一个窗口。 TBI 用于未来干预。我们假设与濒死体验中的神经变性相关的蛋白质， 例如 Aß 以及与 NDE 相关的 miRNA 有可能成为 TBI 和 相关症状。为了检验这一假设，我们将利用我们的前瞻性纵向研究 超过 1200 名海军陆战队员的战斗部署效果，其中 176 名经历了轻度/中度部署相关的影响 创伤性脑损伤。本研究收集了1个月的身心健康状况、神经认知表现和血液样本 部署到阿富汗之前和之后 4-6 个月。我们将使用 150 个 TBI 样本，其中 150 没有 TBI 历史的匹配对照样本可完成 2 个目标。目标 1 将检查效用 濒死体验中的细胞骨架和神经元蛋白可识别 TBI 以及脑震荡后的持续情况 症状和认知能力下降。候选神经退行性蛋白包括 tau、Aß、neurogranin、 神经丝轻链和钙蛋白酶切割的 αII-血影蛋白 N 末端片段。研究还将利用 这些前瞻性样本用于检查受伤前后 NDE 蛋白质的变化是否反映了症状 变化，为这些蛋白质在 TBI 致病过程中提供潜在的因果推论。目标2将 使用公正的发现方法来识别与 TBI 相关的新 miRNA 症状和神经认知能力下降。小RNA测序将对外泌体RNA进行。 与 TBI 相关的 miRNA 将使用 RT-qPCR 进行验证，并在独立样本集中进行复制。 顶尖候选人将接受受伤前后的变化检查，以了解这些变化的贡献 损伤后致病过程的标记。这项研究有很大的潜力提供可访问的、 TBI 和相关症状的定量生物标志物，以及确定潜在的功能目标 干涉。 ！ ！