Investigating the interactions between viral infection, Tau pathology, and neuroinflammation

研究病毒感染、Tau 病理学和神经炎症之间的相互作用

基本信息

批准号：
10746267
负责人：
Kristen Emily Funk
金额：
$ 128.1万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10746267
关键词：
Acceleration Acute Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Attenuated Brain Cell Culture System Data Deposition Development Environment Environmental Risk Factor Exhibits Exposure to Extracellular Space Flow Cytometry Genes Goals Human Immune response Impaired cognition Infection Inflammation Inflammatory Response Kunjin virus Link MAPT gene Measures Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroimmune Neuroimmune system Neurons Pathogenesis Pathology Pattern Phosphorylation Phosphotransferases Positioning Attribute Process Productivity Proteins Research Risk Risk Factors Role Senile Plaques System Testing Transgenic Mice Transgenic Organisms Viral Viral Encephalitis Viral Load result Virus Virus Diseases Virus Replication West Nile virus abeta accumulation abeta deposition antimicrobial peptide cytokine epidemiologic data epidemiology study experimental study extracellular hyperphosphorylated tau in vivo insight microbial mouse model neuroinflammation neuron loss neurotropic overexpression pathogen pathogenic bacteria pathogenic virus protein aggregation response tau Proteins tau aggregation tau interaction tau-1 transcriptome sequencing

项目摘要

Project Summary Increasing evidence points to the neuroimmune system as a primary contributor to Alzheimer’s disease (AD). Environmental factors that increase neuroinflammation, including viral infections, correlate with risk of AD; however, the mechanisms by which microbial infections promote AD are not well understood. AD is defined by the presence of two hallmark pathologies—extracellular senile plaques composed of aggregated amyloid beta peptide (Aβ) and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule associated protein tau. Recent studies have suggested that Aβ may act as an antimicrobial peptide, in which its aggregation can restrict microbial infection by trapping it in the extracellular space. We hypothesize that as an intracellular protein, Tau may act as an antimicrobial peptide against viruses, which are obligate intracellular pathogens. Our preliminary data shows that following intracranial inoculation with an attenuated strain of West Nile virus, Kunjin virus (KUNV), Tau becomes hyperphosphorylated and aggregates. Furthermore, transgenic mice expressing elevated levels of aggregation-prone Tau show reduced viral burden in their brains. Here we propose to study the interactions between viral infection, Tau pathology, and neuroinflammation using a murine model of encephalitic KUNV infection. Aim 1 will determine whether viral infection increases Tau pathology by measuring aggregation, phosphorylation, and truncation. Aim 2 will assess the impact of Tau aggregation on viral replication and whether Tau interacts directly with viral components. Aim 3 will examine the effect of Tau pathology on the neuroinflammatory response to viral infection. Together, these experiments will determine whether viral infection impacts the development of Tau pathology and the role of Tau pathology in modulating the neuroimmune response to viral infection. Successful completion of this project will establish a mechanistic link between AD and viral pathogens.

项目摘要越来越多的证据表明神经免疫系统是阿尔茨海默氏病（AD）的主要贡献者。增加神经炎症（包括病毒感染）的环境因素与AD风险相关；但是，微生物感染促进AD的机制尚不清楚。广告定义存在两种标志性病变 - 由聚集的淀粉样蛋白β组成肽（Aβ）和细胞内神经原纤维缠结，由高磷酸化微管组成相关蛋白质tau。最近的研究表明，Aβ可以充当抗菌胡椒，其中它的聚集可以通过将微生物感染捕获在细胞外空间中来限制微生物感染。我们假设这是 tau是细胞内蛋白质，可以作为针对病毒的抗菌胡椒病原体。我们的初步数据表明，在颅内接种后，西部菌株衰减应变尼罗河病毒，昆金病毒（kunv），tau变为高磷酸化和聚集体。此外，转基因表达较高聚集的tau水平升高的小鼠在大脑中显示出病毒伯嫩的降低。我们在这里提出使用鼠类使用鼠的病毒感染，tau病理学和神经炎症之间的相互作用的提议 AIM 1将确定病毒感染是否通过测量聚集，磷酸化和截断。 AIM 2将评估Tau聚合对病毒复制以及tau是否与病毒成分直接相互作用。 AIM 3将检查Tau的效果关于病毒感染的神经炎症反应的病理学。这些实验将共同确定病毒感染是否影响tau病理的发展和tau病理在调节中的作用对病毒感染的神经免疫反应。成功完成该项目将建立机械 AD和病毒病原体之间的联系。