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.

摘要