Impact of TBI and Cognitive Decline on Alzheimer's Disease Brain-Derived Exosome Cargo
TBI 和认知能力下降对阿尔茨海默病脑源性外泌体货物的影响
基本信息
- 批准号:10662883
- 负责人:
- 金额:$ 194.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAgeAge-associated memory impairmentAgingAlzheimer disease detectionAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmyloid beta-ProteinAstrocytesAttentionAwardBiological AssayBiological MarkersBloodBrainCellsCerebrospinal FluidChronicClinical TrialsCognitionCognitiveComplementCytoskeletonDataDiagnosisDiseaseDizygotic TwinsEligibility DeterminationEndosomesGeneticGenotypeHeritabilityImpaired cognitionIndividualInflammatoryInjuryLiquid substanceLongitudinal cohort studyMagnetic Resonance ImagingMembraneMolecularMonozygotic twinsNatureNerve DegenerationNeurodegenerative DisordersNeuronal DysfunctionNeuronal InjuryNeuronsPathologicPathologyPathway interactionsPeripheralPhasePlasmaPlasma ProteinsPost-Traumatic Stress DisordersProteinsProteomicsRecording of previous eventsRiskSamplingSurfaceSynapsesTestingTraumatic Brain InjuryTwin Multiple BirthTwin StudiesVariantVesicleVeteransVietnamagedapolipoprotein E-4biobankbiomarker identificationbiomarker performancecell typecognitive changecohortcomorbiditycytokineexosomeexperiencehuman old age (65+)mental functionmiddle ageneurograninneuroimagingneuropathologynovelpersistent symptomphenotypic dataspecific biomarkerstau Proteinstau-1tooltreatment trialvesicular release
项目摘要
PROJECT SUMMARY ABSTRACT
Exosomes remove proteins and cellular substituents, and also shuttle protein cargo between cells and also to
the periphery. Unlike freely circulating proteins, exosomes are identified by surface markers that include
designations of cell type origin. Astrocyte and neuronally-derived exosomes (ADEs and NDEs, respectively)
from plasma are identified by specific membrane markers, providing an accessible substrate to identify
biomarkers and mechanisms of neuropathology. The potential for NDEs to identify TBI-related biomarkers
however is just beginning to be explored.
Our lab has a large focus on exosome biomarkers in TBI and neurodegeneration. Our data demonstrate
that Alzheimer's disease (AD) neuropathological proteins, amyloid-beta and phospho-tau are sequestered in
NDEs and are more sensitive biomarkers of AD than free proteins in native plasma. In terms of Veterans with
TBI, we and others have found that NDEs have increased levels of Aβ, proteins associated with neuronal injury
and synaptic proteins. We have also shown that complement protein cargo in ADEs is also associated with
AD. Although exciting, these studies represent relatively small studies in samples from younger individuals
with limited information about the relationship between exosome protein cargo and functional changes. To
examine CNS-enriched exosome proteins as biomarkers of TBI and associated cognitive decline in older
individuals, we will leverage banked plasma samples from the Vietnam Era Twin Study of Aging (VETSA), a
longitudinal cohort study of US Veterans who had a mean age of 56 at the first assessment wave and 67 at the
most recently completed third assessment. In this Merit Award proposal we propose to determine the utility of
neurodegenerative disease proteins within NDEs as biomarkers to predict cognitive change in aging twin
Veterans with post-traumatic stress disorder and TBI and also to identify the mechanisms underlying the
relationship between inflammatory pathways, cognition and neurodegeneration associated with TBI and PTSD
in VETSA. Our overarching hypothesis is that remote TBI is associated with abnormalities in cytoskeletal and
neuronal proteins in circulating NDEs. We also hypothesize that remote TBI causes chronic changes in central
inflammatory tone which leads to abnormalities in complement and cytokine proteins in circulating ADEs
项目概要 摘要
外泌体去除蛋白质和细胞取代基,还在细胞之间运送蛋白质货物,并将蛋白质运送到
外围。与自由循环的蛋白质不同,外泌体是通过表面标记来识别的,包括
细胞类型起源的名称。星形胶质细胞和神经源性外泌体(分别为 ADE 和 NDE)
通过特定的膜标记来识别血浆中的物质,从而提供可接近的底物来识别
神经病理学的生物标志物和机制。 NDE 识别 TBI 相关生物标志物的潜力
然而才刚刚开始探索。
我们的实验室主要关注 TBI 和神经退行性变中的外泌体生物标志物。我们的数据表明
阿尔茨海默病 (AD) 神经病理蛋白、β 淀粉样蛋白和磷酸 tau 蛋白被隔离在
NDE 和 NDE 是比天然血浆中的游离蛋白更敏感的 AD 生物标志物。就退伍军人而言
TBI,我们和其他人发现濒死体验中 Aβ 水平升高,Aβ 是与神经元损伤相关的蛋白质
和突触蛋白。我们还表明,ADE 中的补体蛋白货物也与
广告。尽管令人兴奋,但这些研究代表了针对年轻个体样本的相对较小的研究
关于外泌体蛋白货物和功能变化之间关系的信息有限。到
检查富含 CNS 的外泌体蛋白作为 TBI 的生物标志物以及老年人相关的认知能力下降
对于个人而言,我们将利用来自越南时代双胞胎衰老研究 (VETSA) 的血浆样本,该研究是一项
对美国退伍军人进行的纵向队列研究,他们在第一波评估时的平均年龄为 56 岁,在第二波评估时的平均年龄为 67 岁。
最近完成了第三次评估。在这个优异奖提案中,我们建议确定
濒死体验中的神经退行性疾病蛋白作为预测衰老双胞胎认知变化的生物标志物
患有创伤后应激障碍和 TBI 的退伍军人,并确定其背后的机制
与 TBI 和 PTSD 相关的炎症通路、认知和神经变性之间的关系
在 VETSA 中。我们的首要假设是,远程 TBI 与细胞骨架和细胞异常有关。
循环濒死体验中的神经元蛋白。我们还假设远程 TBI 会导致中枢神经系统的慢性变化。
炎症张力导致循环 ADE 中补体和细胞因子蛋白异常
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Victoria B Risbrough其他文献
Victoria B Risbrough的其他文献
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{{ truncateString('Victoria B Risbrough', 18)}}的其他基金
Validation of PTSD signals across multiple biological domains for the development of diagnostic biomarkers for PTSD in military populations to improve clinical care of Veterans
跨多个生物领域验证 PTSD 信号,以开发军人群体中 PTSD 的诊断生物标志物,从而改善退伍军人的临床护理
- 批准号:
10617231 - 财政年份:2022
- 资助金额:
$ 194.82万 - 项目类别:
Validation of PTSD signals across multiple biological domains for the development of diagnostic biomarkers for PTSD in military populations to improve clinical care of Veterans
跨多个生物领域验证 PTSD 信号,以开发军人群体中 PTSD 的诊断生物标志物,从而改善退伍军人的临床护理
- 批准号:
10365835 - 财政年份:2022
- 资助金额:
$ 194.82万 - 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10588850 - 财政年份:2022
- 资助金额:
$ 194.82万 - 项目类别:
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:
10292911 - 财政年份:2018
- 资助金额:
$ 194.82万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 194.82万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 194.82万 - 项目类别:
Role of COMTval158met in PTSD risk and treatment response
COMTval158met 在 PTSD 风险和治疗反应中的作用
- 批准号:
8730388 - 财政年份:2014
- 资助金额:
$ 194.82万 - 项目类别:
Role of COMTval158met in PTSD risk and treatment response
COMTval158met 在 PTSD 风险和治疗反应中的作用
- 批准号:
8967100 - 财政年份:2014
- 资助金额:
$ 194.82万 - 项目类别:
Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities
破碎的早期生活经历、异常的电路成熟、情感脆弱
- 批准号:
10595601 - 财政年份:2013
- 资助金额:
$ 194.82万 - 项目类别:
Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities
破碎的早期生活经历、异常的电路成熟、情感脆弱
- 批准号:
10379271 - 财政年份:2013
- 资助金额:
$ 194.82万 - 项目类别:
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