Explore roles of HSV-1 in Alzheimer's disease using mouse models

使用小鼠模型探索 HSV-1 在阿尔茨海默病中的作用

基本信息

批准号：
10629403
负责人：
Pinghui Feng
金额：
$ 79.9万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629403
关键词：
Acceleration Affect Aging Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient American Biological Process Brain Cells Cognition Collaborations Dementia Development Disease Economic Burden Environmental Risk Factor Enzymes Epithelium Etiology General Population Herpes Simplex Infections Herpesviridae Herpesviridae Infections Herpesvirus 1 Homeostasis Host Defense Human Immune Evasion Immunocompetent Impairment Individual Infection Innate Immune Response Laboratories Late Onset Alzheimer Disease Mediating Memory Metabolic Metabolism Microbe Modality Molecular Mouse Strains Mus Natural Immunity Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathway interactions Patients Pattern Population Prevention Primary Infection Process Proteins Resistance Risk Factors Role Simplexvirus Structure of trigeminal ganglion Translating Viral Viral Physiology Virion Virus Replication Work aging brain anti aging brain tissue cofactor cytosolic receptor deamidation defined contribution exosome genetic makeup human old age (65+)human pathogen in vivo innovation insight interest latent infection lytic replication microbial mouse model mutant neurotropic nicotinamide phosphoribosyltransferase pathogen social synergism

项目摘要

Abstract Dementia is the progressive loss in memory and cognition of the brain. Alzheimer’s disease (AD) is the leading cause of dementia in those over the age of 65. Currently, there are ~5.6 million Americans age 65 and older have AD, and the projected AD patients will double by 2050. The social and economic burden of neurodegenerative diseases is enormous and no cure or prevention is available to date. Late onset AD accounts more than 98% of all AD cases and is a multifactorial disease, with aging being the most prominent risk factor. In addition to the genetic makeup of a patient, environmental factors, such as microbial infection, contribute significantly to the development and outcome of AD. Herpesviruses are ubiquitous in human and their infection is often asymptomatic in immune- competent individuals. Recent studies suggest a causal role of several herpesviruses, particularly herpes simplex virus 1 (HSV-1), in AD and other related dementia. How HSV-1 contributes to AD pathogenesis is not well understood. In studying host innate immunity against herpesvirus, we discovered that NAMPT, the rate-limiting enzyme of the salvage NAD synthesis pathway, potently restricts HSV-1 lytic replication. Loss of NAMPT greatly increases HSV-1 replication in mice. To counteract the NAMPT-mediated restriction, HSV-1 deploys deamidation to inactivate NAMPT and promote viral replication. Collateral to the HSV-1-induced immune evasion, deamidated NAMPT is severely impaired in synthesizing NAD+. Thus, HSV-1-induced NAMPT deamidation and subsequent impaired salvage synthesis of NAD+ likely contribute to the HSV-1-induced neurodegeneration. Interestingly, aging also induces NAMPT deamidation in the brain. In this study, we will delineate the role of deamidation in host defense and salvage NAD+ synthesis in neurons and in mice. We will also determine how aging and HSV-1 infection synergize to promote NAMPT deamidation and NAD+ depletion, thus fueling neurodegeneration in normal mouse strains. Finally, we will develop a modality to resist NAMPT deamidation that impedes or reverts neurodegeneration and AD development. This study will elucidate an innovative mechanism by which collateral damage of viral immune evasion and aging collaborate to induce neurodegeneration, offering new insight into possible avenues to thwart AD and other neurodegenerative diseases associated with aging and microbial infection.

抽象的痴呆是记忆和大脑认知的逐渐丧失。阿尔茨海默氏病（AD）是65岁以上的痴呆症的主要原因。目前，有〜5.6 65岁及以上的百万美国人有AD，预计的广告患者到2050年将翻一番。神经退行性疾病的社会和经济燃烧是巨大的，没有治愈或预防迄今为止可用。延迟发作广告帐户超过所有广告案例的98％以上，是一个多因素疾病，老龄化是最突出的危险因素。除了通用患者的构成，环境因素，例如微生物感染，可显着贡献达到广告的发展和结果。疱疹病毒在人类中无处不在，其感染通常是渐近的。能干的个人。最近的研究表明，几种疱疹病毒的因果作用，特别是AD和其他相关痴呆症中的单纯疱疹病毒1（HSV-1）。如何HSV-1 对AD发病机理的贡献尚不清楚。在研究宿主先天免疫力时反对疱疹病毒，我们发现nampt是挽救NAD合成的速率限制酶途径，可能限制了HSV-1裂解复制。 NAMPT的损失大大增加了HSV-1 小鼠复制。为了抵消NAMPT介导的限制，HSV-1部署了死亡使NAMPT失活并促进病毒复制。 HSV-1诱导的免疫的抵押品逃避，脱膜NAMPT在合成NAD+时严重受损。这是HSV-1引起的 NAMP HSV-1诱导的神经变性。有趣的是，衰老还引起NAMPT脱氨酸大脑。在这项研究中，我们将描述死亡在宿主防御和抢救中的作用 NAD+神经元和小鼠的合成。我们还将确定衰老和HSV-1感染如何协同作用以促进NAMPT死亡化和NAD+部署，从而加剧了神经退行性在正常的小鼠菌株中。最后，我们将发展一种抵抗Nampt死亡的方式阻碍或恢复神经变性和AD开发。这项研究将阐明病毒免疫进化和衰老的附带损害的创新机制合作以诱导神经退行性，为阻碍可能的途径提供新的见解 AD和其他与衰老和微生物感染相关的神经退行性疾病。