肾上腺素能控制响应流感的 CD8 T 细胞的昼夜节律-猫眼课题宝

肾上腺素能控制响应流感的 CD8 T 细胞的昼夜节律

批准号：

10743822

负责人：

John David FARRAR

金额：

$57.78万

依托单位：

UT SOUTHWESTERN MEDICAL CENTER

依托单位国家：

美国

项目类别：

财政年份：

2023

资助国家：

美国

项目状态：

未结题

起止时间：

2023-07-01 至 2028-06-30

来源：

https://reporter.nih.gov/project-details/10743822

关键词：

ADRB2 gene ARNTL gene Acceleration Acute Adrenergic Agents Adrenergic Receptor Area Arrhythmia Binding Biological Clocks Biological Process CAR T cell therapy CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Circadian Dysregulation Circadian Rhythms Circadian gene expression Communicable Diseases Cues Darkness Development Disease Effector Cell Epinephrine Exhibits Frequencies Gene Expression Genes Goals Health Human Immune Immune response Immunity Infection Inflammation Inflammatory Influenza Influenza A virus Jet Lag Syndrome Light Mammals Measures Mediating Modality Molecular Mus Nature Neurons Neurotransmitter Receptor Neurotransmitters Norepinephrine Outcomes Research Pathway interactions Peripheral Phase Physiology Play Property Publishing Pulmonary Inflammation Role Severity of illness Signal Transduction Sympathetic Nervous System T cell response T-Cell Development T-Lymphocyte T-bet protein Testing Therapeutic Intervention Time Tissues Vaccine Design Viral Pathogenesis Viral Respiratory Tract Infection Viral Vaccines Virus Virus Diseases Virus Replication adaptive immunity anti-cancer antiviral drug development beta-2 Adrenergic Receptors circadian effector T cell human disease improved in vivo influenza infection interest light entrainment lung injury mouse model pathogen public health relevance receptor response targeted treatment therapy design virtual

中文摘要

翻译

项目总结这项应用试图了解昼夜节律如何控制T细胞对流感感染的免疫通过交感神经系统传递的信号。昼夜节律是一种生物钟在哺乳动物中，这些节律在整个生命周期中系统地同步通过交感和副交感神经元传递的信号传递给身体。我们最近的研究发现了一种 CD2-肾上腺素能受体在β+T细胞对病毒感染的溶细胞反应中的意外作用。此外，我们发现CD8+T细胞上ADRB2的选择性缺失严重扰乱了昼夜节律基因表达和振荡频率作为明/暗夹带的函数。这项提案将考验假设CD8+T细胞中通过ADRB2的信号调节昼夜节律基因，并且这些基因是协调T细胞对流感感染做出反应所必需的。目标1将区分角色在CD8介导的流感感染期间肺部炎症中ADRB2及其下游核心时钟的研究。目标2 将决定时差如何影响CD8+T细胞对流感的反应。这项提议测试了一个非常直接的- 前瞻假说，如果得到支持，将是第一个将昼夜节律夹带受体与下游T细胞对流感做出反应。这项研究的结果将大大推动我们的对调节流感免疫反应和改良小鼠的环境途径的认识病毒致病模型和疫苗设计。

英文摘要

PROJECT SUMMARY This application seeks to understand how circadian rhythms control T cell immunity to influenza infection through signals delivered by the sympathetic nervous system. Circadian rhythms are biological clocks that are entrained by light/dark cycles, and in mammals, those rhythms are synchronized systemically throughout the body via signals delivered by sympathetic and parasympathetic neurons. Our recent studies uncovered an unexpected role for the β2-adrenergic receptor in cytolytic responses of CD8+ T cells to a virus infection. Further, we found that selective deletion of the Adrb2 on CD8+ T cells profoundly disrupted circadian gene expression and oscillation frequencies as a function of light/dark entrainment. This proposal will test the hypothesis that the signaling through the ADRB2 in CD8+ T cells regulates circadian rhythm genes, and that those genes are required for orchestrated T cell responses to influenza infection. Aim 1 will distinguish the roles of the Adrb2 and downstream core clock in CD8-mediated lung inflammation during influenza infection. Aim 2 will determine how jet-lag impacts CD8+ T cell responses to influenza. This proposal tests a very straight- forward hypothesis, which if supported, will be the first to connect a circadian rhythm entrainment receptor to downstream T cells responses to influenza. The outcomes of this research will significantly advance our understanding of environmental pathways that regulate immune responses to influenza and improve mouse models of viral pathogenesis and vaccine design.

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