Alzheimer's Disease associated pathology induced by neurotropic viral infection

嗜神经病毒感染诱发的阿尔茨海默病相关病理

基本信息

批准号：
10381213
负责人：
Eain A Murphy
金额：
$ 62.72万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10381213
关键词：
Alleles Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-42 Amyloid beta-Protein Precursor Antiviral Agents Arginine Automobile Driving Biological Biological Models Cell model Cells Cerebrum Clinical Cognitive Coupled DNA Data Dementia Disease Disease Marker Disease Progression Etiology Exclusion Exons Frequencies Genes Genetic Genetic Transcription Goals HHV-6A Herpesviridae Herpesviridae Infections Herpesvirus 1 Human Impaired cognition Individual Infection Integration Host Factors Interdisciplinary Study Investigation Kinetics Label Link Lytic Lytic Phase Messenger RNA Modeling Monitor Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Normal tissue morphology Organoids Outcome Pathogenesis Pathogenicity Pathology Patients Physiological Population Post-Translational Protein Processing Predisposition Production Protein Isoforms Protein Kinase Proteins Protocols documentation RNA RNA Splicing Reporter Resolution Risk Running Serine Severities Spices Synapses System Tauopathies Techniques Testing Time Tissues Transcript Tropism Uracil phosphoribosyltransferase Viral Viral Pathogenesis Virus Virus Diseases Work abeta accumulation amyloid precursor protein processing apolipoprotein E-4 clinically relevant combat established cell line gene correction genetic risk factor induced pluripotent stem cell insight latent infection mRNA Precursor nervous system infection neurotropic neurotropic virus new therapeutic target novel pathogen pathogenic virus permissiveness relating to nervous system single cell sequencing spatial relationship tau Proteins tau aggregation tau expression tau phosphorylation tau-1 transcriptome

项目摘要

SUMMARY Genetic risk factors for Alzheimer's Disease can predict the increased likelihood of acquiring the disease yet it is becoming more evident that external factors are involved in the neurodegenerative disease progression. Recently two herpesviruses have been implicated in this disorder as they have been found in diseased tissues of Alzheimer's patients. Human herpes simplex virus 1 (HSV-1) and Human Herpesvirus 6a (HHV6a) are neurotropic herpesviruses that establish both lytic and lifelong latent infections of the nervous system. How these viral pathogens alter the outcome of neurodegenerative disease remains uncharacterized. Alzheimer's Disease is marked by distinct alterations of host proteins including the misfolding of Tau. Using a novel human iPSC-derived 3D cortical model system, we observed altered splicing of the mRNA that encodes Tau. Additionally, we observe a viral infection dependent increase in the accumulation of phospho-Tau, a post translational modification indicating the misfolding of Tau. These preliminary findings support the hypothesis that viral infections directly impact the host cell microenvironment resulting in changes in Alzheimer's Disease markers. The overarching goal of these studies is to identify infectious etiological agents that impact either the severity or frequency of Alzheimer's Disease progression. The objective of this proposal is to define the biological impact of neurotropic herpesvirus infections on accumulation of known drivers of Alzheimer's disease within a physiologically relevant model system. Our first aim will identify and define viral dependent changes within multiple host proteins involved in neurodegeneration. This will for the first time, a direct link between neurotropic virus infections and pathogenic neurodegenerations in cells of clinical relevance. The second aim will use novel RNA labeling protocols to profile the transcriptome from only infected cells within the 3D organoids and will utilize single cell sequencing to characterize the tropism of these neurotropic viruses. The third aim will utilize 3D organoids that harbor known genetic risk factor mutations found in the onset of Alzheimer's Disease and will determine if herpesviruses amplify the onset of neurodegenerative progression. Successful completion will clearly define the viral factors that influence Alzheimer's disease and will provide insight in pathogenic mechanisms that extend beyond Alzheimer's Disease.

概括阿尔茨海默病的遗传风险因素可以预测患该病的可能性增加，但它越来越明显的是，外部因素参与了神经退行性疾病的进展。最近在患病组织中发现了两种疱疹病毒与这种疾病有关阿尔茨海默氏症患者。人类单纯疱疹病毒 1 (HSV-1) 和人类疱疹病毒 6a (HHV6a) 是嗜神经性疱疹病毒，可引起神经系统的溶解性感染和终生潜伏性感染。如何这些病毒病原体改变神经退行性疾病的结果仍然未知。阿尔茨海默氏症疾病的特点是宿主蛋白的明显改变，包括 Tau 蛋白的错误折叠。使用新奇的人类在 iPSC 衍生的 3D 皮质模型系统中，我们观察到编码 Tau 的 mRNA 剪接发生了改变。此外，我们观察到病毒感染依赖性磷酸-Tau 积累的增加，这是一种后翻译修饰表明 Tau 的错误折叠。这些初步发现支持了这一假设病毒感染直接影响宿主细胞微环境，导致阿尔茨海默病的变化标记。这些研究的首要目标是确定影响以下任一方面的传染性病原体：阿尔茨海默病进展的严重程度或频率。该提案的目标是定义嗜神经性疱疹病毒感染对已知阿尔茨海默病驱动因素积累的生物学影响生理相关模型系统内的疾病。我们的首要目标是识别和定义病毒依赖性参与神经变性的多种宿主蛋白的变化。这将是第一次直接链接嗜神经病毒感染与临床相关细胞中的致病性神经变性之间的关系。这第二个目标是使用新颖的 RNA 标记方案来分析仅受感染细胞的转录组 3D 类器官，并将利用单细胞测序来表征这些嗜神经病毒的向性。第三个目标将利用 3D 类器官，这些类器官含有在疾病发作时发现的已知遗传风险因素突变。阿尔茨海默氏病并将确定疱疹病毒是否会放大神经退行性进展的发生。成功完成将清楚地定义影响阿尔茨海默病的病毒因素，并将提供对阿尔茨海默病以外的致病机制的深入了解。