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病原微生物可能导致疾病的发生或进展 阿尔茨海默病（AD），尽管研究结果尚无定论，但有微生物相关抗原的报道 来自疱疹病毒和疏螺旋体等多种实体。最近的大规模努力，例如 NIH 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药物 生成大型、特征明确的 AD 队列和对照的测序数据。这些数据呈现出新的 有机会直接从临床样本中检测病毒种类的存在并采取病毒措施 物种丰度进入最分子网络和临床特征的背景。我们计划在此基础上 我们的初步工作已确定特定疱疹病毒科物种的丰度持续增加 AD 患者死后脑组织，并证明病毒对 AD 相关分子的调节， 遗传和临床病理网络。该提案的目的旨在阐明遗传、 转录组和蛋白质组宿主网络赋予这些AD-认知和神经病理学弹性 相关病毒种类，目的是确定治疗 AD 的新治疗机会。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、淀粉样蛋白斑密度、神经原纤维缠结严重程度或临床痴呆的诊断相关 评级，并识别能够修改这些关系的主机网络。通过对因果关系进行建模 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（以及它们适当的 扰）作为面对病毒感染时恢复力的潜在中介。我们将验证遗传和小 病毒感染的大脑类器官系统的分子扰动，监测病毒抵抗力的变化 感染性、AD 相关神经病理学标记物和宿主转录组学，包括靶向活性 弹性网络。本研究的预期结果是识别和评估特定的宿主分子 能够调节宿主对 AD 相关感染的反应的网络和小分子 病毒。