Modulation of Alzheimers disease by Herpes simplex virus infection

单纯疱疹病毒感染对阿尔茨海默病的调节

• 批准号: 10408076
• 负责人: Martin C Darvas
• 金额: $ 51.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408076
• 关键词: APBA2 gene; APPBP2 gene; ATRX gene; Affect; Age; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Area; Behavioral; Biology; Brain; Brain region; Clinical; Cognition; Computer Models; DNA; Data; Data Set; Dementia; Development; Elderly; Environmental Risk Factor; Etiology; Event; Family member; Female; Gender; Gene Expression; Gene Expression Regulation; Genes; Genetic Determinism; Genetic Transcription; Genotype; Glycoproteins; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 6; Infection; Investigation; Link; Medicine; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Neurodegenerative Disorders; Pathologic; Pathology; Pathway Analysis; Patients; Phosphotransferases; Play; Procedures; Proteins; Research; Role; Senile Plaques; Simplexvirus; Slice; Testing; Therapeutic; Time; Transcript; Viral; Viral Physiology; Virus Diseases; adeno-associated viral vector; amyloid pathology; amyloid precursor protein processing; antimicrobial peptide; apolipoprotein E-4; base; behavior change; beta-site APP cleaving enzyme 1; chronic infection; comparative; differential expression; endophenotype; experience; experimental study; genetic association; immune function; in vivo; in vivo Model; insight; intraperitoneal; lens; male; mimicry; mortality; mouse model; multidisciplinary; neuropathology; neurotropic; novel; presenilin-1; tau Proteins; transcription factor; transcription regulatory network; transcriptome sequencing; transcriptomics

Alzheimer 's disease (AD) affects millions of Americans and causes significant morbidity and mortality. Although genetic determinants of AD have been a major focus of research over the last three decades, there is limited insight into co-factors that contribute to AD pathology and progression. Recent genetic associations implicating alterations in innate immunity to risk for AD, suggest that environmental factors, such as infection, may modulate brain immune function and could also play a role in AD. Previous studies have suggested that chronic infection of neurotropic herpesviruses could be one factor that contributes to the development of AD pathology. In particular, herpes simplex virus type 1 (HSV-1) DNA has been found in AD brains and in β-amyloid plaques. Through careful multiscale network analysis of the large RNA-seq. datasets within the Accelerating Medicines Partnership-AD (AMP-AD) consortium, we have observed an increased abundance of transcripts derived from several herpesvirus family members across multiple brain regions from subjects with AD, and we have found that HSV-1 expression was associated with the clinical dementia score of AD patients. Notably, this observation has been replicated across three independent AMP- AD RNA-seq studies. We found evidence of viral mimicry upon viewing our viral/AD-associated genes through the lens of transcriptional regulatory networks. We have identified candidate transcription factors and their downstream targets associated with viral expression, as well as kinases that regulate activity of those transcription factors. Additionally, HSV-1 transcripts were associated with increased expression of several key regulators of APP processing. We propose to explore this provocative transcriptomic data using a set of experiments that will determine if expression of herpesviruses encoded proteins and HSV-1 infection contributes to the development and progression of AD. We hypothesize that neurotropic herpesvirus infection alters transcriptional regulatory networks of known AD genes to drive pathology. Two parallel lines of investigation will be conducted. The first will combine the experience of the multidisciplinary team with neuropathology, HSV-1 biology, HSV infection in mice and RNA-seq analysis to directly ask (1) whether active viral infection with HSV-1 can alter AD pathology or enhance preexisting pathology in mouse models of AD pathology, and (2) perform longitudinal assessments of changes in AD-relevant RNA expression in HSV-1 infected AD mice. Through our comparative approach and computational modeling, we will characterize how HSV-1 infection impacts known AD pathways and neuropathological features. The second will leverage the use of adeno-associated viral vectors to express candidate transcription factors identified in AMP-AD RNA-seq. studies in: brain slice cultures and mouse models of AD pathology. As a result, we will establish new models and a testing procedure including ex vivo and in vivo models that allow us to explore our provocative RNA-seq. AMP-AD data in way that could rapidly inform a novel anti-viral based therapeutic approach to AD.

阿尔茨海默病（AD）影响数百万美国人并导致显著的发病率和死亡率。尽管AD的遗传决定因素在过去三十年中一直是研究的主要焦点，但对有助于AD病理和进展的辅助因素的了解有限。最近的遗传协会牵连改变先天免疫AD的风险，表明环境因素，如感染，可能会调节脑免疫功能，也可能在AD中发挥作用。以往的研究表明，嗜神经性疱疹病毒的慢性感染可能是导致AD病理发展的因素之一。特别是，在AD脑和β-淀粉样蛋白斑块中发现了1型单纯疱疹病毒（HSV-1）DNA。通过对大型RNA-seq.在加速药物伙伴关系-AD（AMP-AD）联盟内的数据集中，我们已经观察到来自AD受试者的多个脑区域的来自几种疱疹病毒家族成员的转录物的丰度增加，并且我们已经发现HSV-1表达与AD患者的临床痴呆评分相关。值得注意的是，这一观察结果在三个独立的AMP中得到了重复- AD RNA-seq研究。我们通过观察我们的病毒/AD相关基因，发现了病毒模仿的证据。 转录调控网络的透镜。我们已经确定了候选转录因子及其与病毒表达相关的下游靶点，以及调节这些转录因子活性的激酶。此外，HSV-1转录本与APP加工的几种关键调节因子的表达增加有关。我们建议使用一组实验来探索这种挑衅性的转录组学数据，这些实验将确定疱疹病毒编码蛋白的表达和HSV-1感染是否有助于AD的发展和进展。我们假设嗜神经性疱疹病毒感染改变了已知AD基因的转录调控网络，从而导致病理改变。将进行两条平行的调查路线。第一个将联合收割机结合多学科团队的经验与神经病理学，HSV-1生物学，小鼠HSV感染和RNA-seq分析，直接询问（1）HSV-1的活性病毒感染是否可以改变AD病理学或增强AD病理学小鼠模型中的既存病理学，以及（2）对HSV-1感染AD小鼠中AD相关RNA表达的变化进行纵向评估。通过我们的比较方法和计算建模，我们将描述如何 HSV-1感染影响已知的AD途径和神经病理学特征。第二个将利用腺相关病毒载体来表达AMP-AD RNA-seq中鉴定的候选转录因子。研究：脑切片培养和AD病理学小鼠模型。因此，我们将建立新的模型和测试程序，包括离体和体内模型，使我们能够探索我们的挑衅性RNA-seq。AMP-AD数据的方式，可以迅速通知一种新的抗病毒为基础的治疗方法，以AD。