Temporal responses in host-virus interactions

宿主与病毒相互作用的时间反应

• 批准号: 10580238
• 负责人: Stanislava Chtarbanova
• 金额: $ 44.7万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-07 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580238
• 关键词: Age; Aging; Biological Assay; COVID-19 pandemic; Candidate Disease Gene; Chronic Disease; Communicable Diseases; Complex; Data; Defense Mechanisms; Disease; Drosophila genus; Drosophila melanogaster; Elderly; Ensure; Exhibits; Future; Genes; Genetic; Genetic Transcription; Goals; Human; Hyperactivity; Immune; Immune response; Immune system; Impairment; Incidence; Individual; Infection; Inflammatory; Integration Host Factors; Knowledge; Life; Longevity; Mediating; Modeling; Molecular; Molecular Biology; Molecular Target; Morbidity - disease rate; NF-kappa B; NFKB Signaling Pathway; Organism; Outcome; Pathway interactions; Planets; Play; Population; Predisposition; Prevention strategy; Process; Public Health; RNA; RNA Interference; RNA Virus Infections; RNA Viruses; Regulation; Reporting; Research; Role; STEM research; Science, Technology, Engineering and Mathematics; Severities; Stimulator of Interferon Genes; Students; System; Testing; Therapeutic; Tissue-Specific Gene Expression; Training; Variant; Viral; Viral load measurement; Virus; Virus Diseases; age related; aged; antiviral immunity; coping; experimental study; fly; gene conservation; gene function; genetic approach; genomic locus; high risk; human old age (65+); immunopathology; improved; in vivo; insight; knock-down; model organism; mortality; mutant; next generation; novel; older patient; overexpression; pathogen; recruit; response; trait; treatment strategy; virus host interaction; young adult

PROJECT SUMMARY In addition of being at higher risk for developing chronic disease, elderly individuals are more vulnerable than younger adults to infectious diseases, including viral infections, and often exhibit higher incidence, severity and mortality rates. Despite numerous advances in understanding the interactions between viruses and their hosts, we lack knowledge about the processes underlying these relationships as a function of age. With the unprecedented numbers of older individuals on the planet, a major goal is to ensure appropriate preventive and treatment strategies leading to a longer, healthier life. Consequently, there is great need to unravel the fundamental mechanisms that lie beneath the capability of the aged organism to survive infection. In this application, we propose to use the model organism Drosophila melanogaster to investigate the mechanisms that contribute to age-dependent survival of infection with an RNA virus. Precisely, we will use a combination of genetic and molecular approaches to 1) investigate the role inflammatory NF-kB pathways play in immunopathology associated with viral infection at older age 2) conduct functional analysis of a set of evolutionarily conserved genes with no previously reported role in antiviral immunity. Our experiments will focus on studying the role of infection tolerance mechanisms as an age-dependent anti-viral defense strategy. We will also seek to determine how the evolutionarily conserved NF-kB inflammatory pathway and possibly other cellular pathways are implicated in the impaired ability of the older host to survive virus infection. This will be done by examining age-dependent outcomes of infection in several mutants for components of the Drosophila IMD NF- kB pathway and in fly lines in which novel candidate genes are being knocked down or overexpressed. Because the underlying genetic and molecular mechanisms are likely to be conserved from flies to humans, we expect these studies to provide important new insights filling the knowledge gap about the interactions of viruses and their older hosts. Our studies could potentially lead to future therapeutic improvements for infected elderly patients. The proposed project also has for a goal to recruit and train a diverse body of students who will represent the next generation of scholars in the science, technology, engineering, and mathematics (STEM).

项目总结 除了罹患慢性病的风险较高外，老年人更容易受到伤害。 比年轻人更容易感染传染病，包括病毒感染，而且往往表现出更高的发病率、严重性 和死亡率。尽管在了解病毒和它们之间的相互作用方面取得了许多进展 作为主人，我们缺乏关于这些关系作为年龄函数的过程的知识。与 由于地球上老年人的数量前所未有，一个主要目标是确保适当的预防和 治疗策略导致更长、更健康的生命。因此，迫切需要解开 老年有机体在感染后存活能力的基本机制。 在此应用中，我们建议使用模式生物果蝇黑腹果蝇来研究 促进RNA病毒感染的年龄相关性存活的机制。准确地说，我们将使用 结合遗传和分子方法1)研究炎症性核因子-kB通路在其中的作用 在与老年病毒感染相关的免疫病理学中2)对一组 进化上保守的基因，以前没有报道过在抗病毒免疫中的作用。我们的实验将集中于 研究感染耐受机制作为年龄相关的抗病毒防御策略的作用。我们会 还试图确定进化上保守的核因子-kB炎症途径以及可能的其他细胞 这些途径与老年宿主在病毒感染后存活的能力受损有关。这将通过以下方式完成 检测果蝇IMD核因子组分的几个突变体感染的年龄相关性结果 Kb途径和在新候选基因被击倒或过度表达的苍蝇系中。因为 我们预计，潜在的遗传和分子机制很可能从苍蝇到人类都是保守的。 这些研究提供了重要的新见解，填补了关于病毒和病毒相互作用的知识空白 他们的老主人。我们的研究可能会为未来感染的老年人带来治疗上的改进 病人。拟议的项目还以招募和培训多样化的学生为目标，这些学生将 代表科学、技术、工程和数学(STEM)领域的下一代学者。