Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to AlzheimerâÂÂs disease associated viruses

识别阿尔茨海默氏病相关病毒的认知和神经病理恢复力的遗传和转录组网络

• 批准号: 10457833
• 负责人: Benjamin Readhead
• 金额: $ 110.47万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457833
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Antibodies; Antibody Repertoire; Antigens; Autopsy; Biological Markers; Biology; Borrelia; Brain region; CRISPR screen; Cause of Death; Cerebrum; Clinic; Clinical; Cognitive; DNA; DNA Markers; DNA Sequence; Data; Data Set; Dementia; Development; Disease; Future; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Risk; Genomics; Goals; Herpesviridae; Human; Immune response; Individual; Infection; Link; Measures; Mediator of activation protein; Medicine; Microbe; Modeling; Molecular; Molecular Genetics; Monitor; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Organoids; Outcome; Outcome Study; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Proteomics; RNA Sequences; Regulation; Reporting; Research Personnel; Resolution; Role; Sampling; Satellite Viruses; Senile Plaques; Severities; Sjogren' s Syndrome; Suggestion; System; Therapeutic; Time; Tissues; United States; United States National Institutes of Health; Viral; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Work; aging brain; antimicrobial; brain tissue; cohort; density; design; drug development; drug repurposing; effective therapy; endophenotype; familial Alzheimer disease; genome-wide; improved; in vitro Model; innovation; insight; molecular diagnostics; multiple omics; neuropathology; next generation sequencing; novel; novel therapeutics; pathogenic bacteria; pathogenic microbe; pathogenic virus; relating to nervous system; resilience; risk stratification; risk variant; small molecule; tau Proteins; trait; transcriptomics; translational study; viral RNA; virome

ABSTRACT Investigators have long suspected that pathogenic microbes might contribute to the onset or progression of Alzheimer's disease (AD) although findings have been inconclusive, with reports of microbe-related antigens from entities as diverse as herpesviruses and borrelia species. Recent large-scale efforts such as the NIH Accelerating Medicines Partnership for Alzheimer's disease (AMP-AD) are generating multiple forms of next- generation sequencing data on large, well-characterized AD cohorts and controls. These data present new opportunities to detect the presence of viral species directly from clinical samples and to put measures of viral species abundance into the context of the most molecular networks and clinical features. We plan to build upon our preliminary work that has identified consistently increased abundance of specific Herpesviridae species in post mortem brain tissue from individuals with AD, and demonstrated viral regulation of AD associated molecular, genetic and clinic-pathological networks. The Aims of this proposal are designed to illuminate the genetic, transcriptomic and proteomic host networks that confer cognitive and neuropathological resilience to these AD- associated viral species, with the goal of identifying novel therapeutic opportunities for the treatment of AD. This requires that we systematically characterize the impact of viral perturbations that are known or suspected to associate with a diagnosis of AD, amyloid plaque density, neurofibrillary tangle severity or clinical dementia ratings, and identify the host networks capable of modifying these relationships. By modelling the causal interactions that relate virus, host and disease, we can conceptualize these host molecules (and their appropriate perturbations) as potential mediators of resilience in the face of viral infection. We will validate genetic and small molecule perturbations of virally infected cerebral organoids systems, monitoring changes in resilience to viral infectivity, AD associated neuropathology markers, and host transcriptomics, including activity of targeted resilience networks. The expected outcome of this study is to identify and evaluate specific host molecular networks and small molecules that are capable of modulating host responses to infection with AD-relevant viruses.

摘要 长期以来，研究人员一直怀疑致病微生物可能导致 阿尔茨海默氏病（AD），虽然研究结果一直没有定论，与微生物相关抗原的报告 从疱疹病毒和疏螺旋体等不同种类的实体中分离。最近的大规模努力，如美国国立卫生研究院 加速阿尔茨海默病药物合作伙伴关系（AMP-AD）正在产生多种形式的下一代- 在大型的、充分表征的AD队列和对照组上生成测序数据。这些数据显示， 有机会直接从临床样本中检测出病毒种类的存在，并对病毒种类进行检测。 物种丰度的背景下，最分子网络和临床特征。我们计划建立在 我们的初步工作已经确定了在人类中特定疱疹病毒科物种的丰度持续增加， 来自AD个体的死后脑组织，并证明了AD相关分子的病毒调节， 遗传和临床病理网络。这项建议的目的是阐明遗传， 转录组和蛋白质组宿主网络，赋予认知和神经病理学的弹性，这些AD- 相关的病毒种类，目的是确定治疗AD的新的治疗机会。这 要求我们系统地描述已知或怀疑的病毒扰动的影响， 与AD诊断、淀粉样斑块密度、神经系统缠结严重程度或临床痴呆相关 评级，并确定能够修改这些关系的主机网络。通过模拟因果关系 通过研究病毒、宿主和疾病之间相互作用，我们可以将这些宿主分子（及其相应的 扰动）作为面对病毒感染时恢复力的潜在介质。我们将验证基因和小 病毒感染的脑类器官系统的分子扰动，监测对病毒的恢复力的变化 感染性、AD相关神经病理学标志物和宿主转录组学，包括靶向 弹性网络。本研究的预期结果是鉴定和评价特定的宿主分子 网络和小分子，能够调节宿主对AD相关感染的反应， 病毒