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

基本信息

批准号：
10005945
负责人：
Martin C Darvas
金额：
$ 57.58万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10005945
关键词：
APBA2 gene APPBP2 gene ATRX gene Affect Age Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk American Amyloid Antiviral Agents 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 network models neuropathology neurotropic novel presenilin-1 tau Proteins transcription factor transcriptome sequencing transcriptomics

项目摘要

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) 影响着数百万美国人，并导致显着的发病率和死亡率。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，但对导致 AD 病理和进展的辅助因素的了解有限。最近的遗传关联表明先天免疫的改变与 AD 风险有关，表明环境因素（例如感染）可能会调节大脑免疫功能，并且也可能在 AD 中发挥作用，之前的研究表明，嗜神经性疱疹病毒的慢性感染可能是一个因素。那特别是，通过对大型 RNA 序列数据集进行仔细的多尺度网络分析，在 AD 大脑和 β-淀粉样斑块中发现了 1 型单纯疱疹病毒 (HSV-1) DNA。 Accelerated Medicines Partnership-AD (AMP-AD) 联盟中，我们观察到来自 AD 受试者多个大脑区域的多个疱疹病毒家族成员的转录本丰度增加，并且我们发现 HSV-1 表达与AD 患者的临床痴呆评分值得注意的是，这一观察结果已在三个独立的 AMP 中得到重复。 AD RNA-seq 研究通过观察我们的病毒/AD 相关基因发现了病毒模仿的证据。我们已经确定了与病毒表达相关的候选转录因子及其下游靶标，以及调节这些转录因子活性的激酶此外，HSV-1 转录物与几个关键调节因子的表达增加有关。我们建议通过一系列实验来探索这一令人兴奋的转录组数据，以确定疱疹病毒编码蛋白和 HSV-1 感染的表达是否有助于 AD 的发生和进展。已知 AD 基因的调控网络驱动病理学，第一个研究将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 分析来直接询问（ 1) HSV-1 的主动病毒感染是否可以改变 AD 病理学或增强 AD 病理学小鼠模型中预先存在的病理学，以及 (2) 通过我们的研究对 HSV-1 感染的 AD 小鼠中 AD 相关 RNA 表达的变化进行纵向评估。比较方法和计算模型，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表达 AMP-AD RNA-seq 研究中确定的候选转录因子：脑切片培养物和 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，使我们能够探索令人兴奋的 AMP-AD 数据，从而快速为基于抗病毒的新型治疗方法提供信息。广告。