Adrenergic control of circadian rhythms in CD8 T cells responding to influenza

肾上腺素能控制响应流感的 CD8 T 细胞的昼夜节律

基本信息

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
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

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

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

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项目摘要

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.

项目摘要该应用程序旨在了解昼夜节律如何控制T细胞免疫对影响力感染通过交感神经系统传达的信号。昼夜节律是生物钟由光/黑暗周期和哺乳动物中，这些节奏在整个整个过程中被系统地同步通过交感神经和副交感神经元传递的信号。我们最近的研究发现了 β2-肾上腺素能受体在CD8+ T细胞对病毒感染的细胞溶解反应中的意外作用。此外，我们发现CD8+ T细胞上ADRB2的选择性删除严重破坏了昼夜节律基因表达和振荡频率是光/黑暗浮雕的函数。该建议将测试假设通过CD8+ T细胞中ADRB2信号传导调节昼夜节律基因，并且这些基因是精心策划的T细胞对影响力感染的反应。 AIM 1将区分角色在影响力感染期间，CD8介导的肺注射中的ADRB2和下游核心时钟目标2 将确定喷气滞后如何影响CD8+ T细胞对影响力的响应。该建议测试非常直接前向假设（如果得到支持）将是第一个将昼夜节律夹带接收者连接到下游T细胞对影响力的反应。这项研究的结果将大大推动我们的了解调节免疫调查以影响和改善鼠标的环境通路病毒发病机理和疫苗设计的模型。