Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to Alzheimer’s disease associated viruses

识别阿尔茨海默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: 10553862
• 负责人: Benjamin Readhead
• 金额: $ 28.88万
• 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/10553862
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Antigens; Borrelia; Cause of Death; Cerebrum; Clinic; Clinical; Cognitive; Data; Dementia; Disease; Genetic; Goals; Herpesviridae; Immune response; Individual; Infection; Measures; Mediator of activation protein; Medicine; Microbe; Modeling; Molecular; Molecular Genetics; Monitor; Neurodegenerative Disorders; Neurofibrillary Tangles; Organoids; Outcome Study; Pathologic; Proteomics; Regulation; Reporting; Research Personnel; Role; Sampling; Satellite Viruses; Senile Plaques; Severities; System; Therapeutic; United States; United States National Institutes of Health; Viral; Virus; Virus Diseases; Work; brain tissue; cohort; density; design; drug development; drug repurposing; effective therapy; neuropathology; next generation sequencing; novel therapeutics; pathogenic microbe; resilience; small molecule; transcriptomics

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.

抽象的 研究人员长期以来一直怀疑致病性微生物可能有助于发作或进展 阿尔茨海默氏病（AD）尽管发现尚无定论，并报道了微生物相关的抗原 来自像疱疹病毒和疏螺旋体物种的潜水员实体。最近的大规模努力，例如NIH 加速阿尔茨海默氏病（AMP-AD）的加速药物伙伴关系正在产生多种形式 对大型，良好的广告群和对照组的生成测序数据。这些数据呈现新的 直接从临床样本中检测病毒物种的存在并放置病毒的机会 物种的丰富性进入了最分子网络和临床特征的背景。我们计划以 我们的初步工作已经确定了在 来自AD个体的尸体脑组织，并证明了AD相关分子的病毒调节， 遗传和临床病理网络。该提案的目的旨在阐明遗传， 转录组和蛋白质组学的宿主网络会召集认知和神经病理学的韧性 相关病毒物种，目的是识别AD治疗的新型治疗机会。这 要求我们系统地表征已知或怀疑的病毒扰动的影响 与AD诊断，淀粉样•斑块密度，神经纤维缠结或临床痴呆症的诊断 评分，并确定能够修改这些关系的主机网络。通过建模因果 与病毒，宿主和疾病相关的相互作用，我们可以概念化这些宿主分子（及其适当的分子 面对病毒感染时，扰动）作为弹性的潜在介体。我们将验证遗传和小 实际感染的脑器官系统的分子扰动，监测病毒的弹性变化 感染性，与AD相关的神经病理学标记和宿主转录组学，包括针对性的活动 弹性网络。这项研究的预期结果是识别和评估特定的宿主分子 能够调节与广告相关的宿主对感染的反应的网络和小分子 病毒。