Neurotropic Viral Infection in CNS Aging and Alzheimer's Disease

中枢神经系统衰老和阿尔茨海默氏病中的神经病毒感染

基本信息

批准号：
10160734
负责人：
Kristen Emily Funk
金额：
$ 24.08万
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：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160734
关键词：
Acute Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology American Amyloid beta-Protein Antigen Presentation Award Behavioral Binding Brain Cell Aging Cell Surface Receptors Central Nervous System Diseases Chronic Cognitive DNA Damage Data Dementia Deposition Development Disease Embryo Encephalopathies Epidemic Epigenetic Process Event Gene Expression Genes Genetic Genetic Polymorphism Goals IL8 gene Immune Impaired cognition In Vitro Individual Infection Infectious Agent Inflammation Inflammatory Innate Immune System Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Lead Ligands Longevity MAPT gene Maintenance Mediating Memory Loss Mentors Microglia Mitotic Modeling Modification Molecular Morbidity - disease rate Mus Mutation Nerve Degeneration Neuraxis Neuroimmune Neurons Pathogenesis Pathologic Pathology Pathway interactions Pattern Peripheral Phagocytosis Phase Process Proliferating Recovery Resolution Risk Risk Factors Role Scientist Signal Transduction Synapses TREM2 gene Telomere Shortening Training Transgenic Mice United States Up-Regulation Viral Viral Encephalitis Virus Diseases West Nile Encephalitis West Nile viral infection West Nile virus cytokine emerging human pathogen epidemiologic data experimental study functional decline genetic signature genome wide association study mortality mouse model multidisciplinary nervous system development neuroimmunology neuroinflammation neuron loss neurotropic novel novel therapeutics overexpression oxidative DNA damage receptor response self-renewal senescence tau Proteins tau aggregation virology

项目摘要

Project Summary Alzheimer's disease (AD) is estimated to affect 5.3 million Americans currently and is expected to rise over the next decade. Neuroinflammation is increasingly recognized as contributing to disorders of the central nervous system (CNS) including AD. Microglial cell surface receptor TREM2 was recently identified from two independent genome-wide association studies to contribute to the risk of developing AD, and previous studies suggested that infectious burden may contribute to the etiopathogenesis of AD. I hypothesize that viral encephalitis may enhance inflammatory events that accelerate the normal processes of CNS aging and contribute to the development of AD pathology. This five-year project has three specific aims that use West Nile virus (WNV) neuroinvasive disease as a model of viral encephalitis. During the K99 mentored phase of this project, Aim 1 will identify mechanisms of microglial-mediated aging processes triggered by WNV encephalitis using a TREM2-/- mouse model. I hypothesize that viral encephalitis triggers neuroinflammatory processes that accelerate replicative senescence in microglia via telomere shortening and inflammatory cytokine expression. Because TREM2 is critical in sensing environmental damage associated molecular patterns, we expect that TREM2-/- microglia will be will be less effective in responding to neuronal damage following viral encephalitis causing increased CNS aging. Aim 2, also during the K99 mentored phase, will identify mechanisms of neuron-mediated aging processes triggered by WNV encephalitis. Data from the Klein lab demonstrate that IL-1 receptor 1 (IL-1R1) signaling is essential for survival from acute neurotropic viral infection. However, inflammatory cytokines including IL-1 and IL-8, which are upregulated via IL-1R1 signaling, contribute to neuronal senescence via DNA damage. Experiments in this Aim will examine the role of IL-1R1 signaling following recovery from WNV encephalitis and during neuronal aging using IL-1R1-/- mice and in vitro primary neuron culture models. During the R00 independent phase of this project, Aim 3 will explore the impact of viral encephalitis on pathological tau accumulation. AD is defined by proteinaceous deposits composed of Aβ and tau. Aβ is known to stimulate chronic inflammation; however, less is known about the role of misfolded tau in the neuroinflammatory cascade, and even less is known is about how neuroinflammation can contribute to tau deposition. I hypothesize that an acute episode of neuroinflammation caused by viral encephalitis may predispose an individual to develop AD pathology. Experiments in this Aim will determine whether viral encephalitis increases the rate at which transgenic mice harboring the Mapt P301L mutation develop tau pathology, identify the impact of tau aggregates on the aging processes in primary microglia, and determine whether IL-1β impacts tau aggregation propensity in primary neurons cultures from Mapt P301L embryonic mice. These studies will give new understanding of the impact of viral encephalitis to processes of aging in the CNS and the development of AD.

项目摘要据估计，阿尔茨海默氏病（AD）目前会影响530万美国人，预计将增加接下来的十年。神经炎症越来越被认为是导致中枢神经的疾病系统（CNS），包括广告。最近从两个独立的全基因组关联研究有助于发展AD的风险，并以前的研究提出感染性烧伤可能有助于AD的病情发生。我假设病毒脑炎可能会增强炎症事件，从而加速CNS衰老和有助于AD病理的发展。这个五年的项目具有三个使用West的特定目标尼罗河病毒（WNV）神经性疾病是病毒脑炎的模型。在K99 Mendored阶段该项目，AIM 1将确定WNV触发的小胶质细胞介导的老化过程的机制使用TREM2 - / - 小鼠模型的脑炎。我假设病毒脑炎会触发神经炎症性通过端粒缩短和炎症加速小胶质细胞中复制感应的过程细胞因子表达。因为TREM2对于感测环境损伤至关重要模式，我们预计TREM2 - / - 小胶质细胞在响应神经元损伤方面的有效性将较低病毒脑炎后导致中枢神经系统衰老增加。 AIM 2（也在K99 MENDORED阶段）将确定WNV脑炎触发的神经介导的衰老过程的机制。来自klein的数据实验室证明IL-1受体1（IL-1R1）信号对于急性神经性病毒的存活至关重要感染。然而，通过IL-1和IL-8在内的炎症细胞因子，包括IL-1和IL-8，通过IL-1R1信号传导进行更新，通过DNA损伤有助于神经元感应。此目标的实验将检查IL-1R1的作用从WNV脑炎中恢复和使用IL-1R1 - / - 小鼠和体外恢复神经元老化后的信号传导原发性神经元培养模型。在该项目的R00独立阶段，AIM 3将探索病毒脑炎对病理tau积累的影响。 AD由蛋白质沉积物定义由Aβ和TAU组成。已知Aβ会刺激慢性炎症。但是，对角色的了解少神经炎性级联反复折叠的tau，甚至更少的是关于神经炎症的方式可以有助于tau沉积。我假设病毒引起的急性神经炎症发作脑炎可能会使个体易于发展AD病理学。这个目标的实验将决定病毒性脑炎是否会增加具有地图P301L突变的转基因小鼠的速率开发tau病理学，确定tau骨料对原发性小胶质细胞衰老过程的影响，以及确定IL-1β是否影响MAP P301L的原代神经元培养物的Tau聚集改善胚胎小鼠。这些研究将使人们对病毒脑炎对过程的影响有了新的了解中枢神经系统的衰老和AD的发展。