The role of circadian clock proteins in innate and adaptive immunity

生物钟蛋白在先天性和适应性免疫中的作用

• 批准号: 10892546
• 负责人: MATTHEW Randall ROSENGART
• 金额: $ 37.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10892546
• 关键词: Actins; Acute; Agonist; Antibody Formation; Antigen Presentation; Attenuated; B cell differentiation; B-Lymphocytes; Bacteria; Biological; Biology; Cell Respiration; Cells; Cellular biology; Central Nervous System; Clock protein; Complex; Cues; Data; Dimensions; Disease; Exposure to; FRAP1 gene; Health; Human; Immune; Immune response; Immunocompetence; In Vitro; Individual; Infection Control; Inflammation; Intra-abdominal; Klebsiella pneumoniae; Light; Mammalian Cell; Mediating; Metabolic; Mitochondria; Modeling; Mononuclear; Natural Immunity; Optics; Organ; Organism; Outcome; PIK3CG gene; Pathway interactions; Patients; Peripheral; Phagocytes; Phenotype; Physiological; Physiology; Pneumonia; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Research; Role; Sepsis; Signal Transduction; Spleen; Stress; Therapeutic; Tissues; adaptive immunity; blue light therapy; cholinergic; circadian; circadian pacemaker; immune function; improved outcome; in vivo; innovation; microbial; monocyte; mouse model; organ injury; programs; recruit; response; rev Protein; septic; systemic inflammatory response

ABSTRACT Within each mammalian cell is a core set of circadian clock proteins that regulate the cellular biology supporting more complex organ physiologies. The central nervous system, entrained by the principle environmental cue – light, synchronizes these peripheral cellular ‘clocks’ across the entire organism, which enables the host organism to anticipate and prepare for the stresses of the active day (e.g., metabolic demands, septic threat). The current evidence, including data derived from our own research program, highlight the profound influence individual clock proteins have on the physiologic capacity with which an organism responds to stress. We first identified that the spectrum of light is a critical determinant of its effects on mammalian biology, and that the short wavelength visible blue spectrum favorably modifies the biology and outcome of sepsis. In murine models of intraabdominal sepsis and Klebsiella pneumoniae (KP) pneumonia, exposure to blue light after sepsis enhanced immune competence, as evidenced by more efficient clearance of bacteria from the septic focus, reduced bacterial dissemination, and attenuated systemic inflammation. The mechanism involved an optic-cholinergic pathway that induced the clock protein Rev-Erba in immune tissues of the spleen and Mj. A Rev-Erba agonist similarly enhance immune function in both in vitro and in vivo studies. Our overarching hypothesis is that the cellular state of the clock protein Rev-Erba is a critical determinant of immune competence and can be modulated to improve the outcome of sepsis. We specifically hypothesize that Rev-Erba regulates the protein machinery supporting the immune phenotype of the mononuclear phagocyte and B cell and is vital to an efficient immune response to microbial threat. In Aim 1 we will study the physiologic and cellular mechanisms by which blue light and the clock protein Rev-Erba regulate monocyte recruitment to the spleen and peripheral tissues and differentiation into a type of monocyte highly efficient in bacterial clearance, using a model of KP pneumonia. In Aim 2, we will explore the mechanisms by which blue light and Rev-Erba modulate B cell PI3K-AKT-mTOR signaling and actin assembly to mediate B cell differentiation, activation, MHC II antigen presentation, and antibody production. As these mechanisms are metabolically demanding and ATP-dependent, we will (Aim 3) determine the mechanisms by which Rev-Erba modulates mitochondrial dynamics to support oxidative metabolism and thereby the phenotype of immune cells during sepsis. The ramifications of light on health and disease remain to be convincingly defined. This proposal will define the biological mechanisms through which circadian clock proteins beneficially alter the host response to acute infectious insult. We will define the dimensions of light and state of clock proteins that are optimally protective and examine their biological relevance and potential therapeutic value in studies of patients with pneumonia.

摘要 在每个哺乳动物细胞内都有一套核心的生物钟蛋白， 支持更复杂的器官生理学。中枢神经系统，被原理所引导 环境提示-光，在整个生物体中调节这些外围细胞“时钟”， 使宿主生物体能够预期并准备活动日的应激（例如，代谢 需求、败血症威胁）。目前的证据，包括来自我们自己研究项目的数据， 强调了个体时钟蛋白对生理能力的深刻影响， 有机体对压力有反应。我们首先发现光的光谱是其影响的关键决定因素 在哺乳动物生物学上，并且短波长可见蓝色光谱有利地修改了 脓毒症的生物学和结局。在腹腔内脓毒症和肺炎克雷伯菌（KP）的小鼠模型中 肺炎，脓毒症后暴露于蓝光增强了免疫能力，证明了更有效的 从脓毒症病灶清除细菌，减少细菌传播， 炎症其机制涉及一个视-胆碱能通路，诱导时钟蛋白Rev-Erba 脾脏和Mj.一种Rev-Erba激动剂在体外同样地增强免疫功能， 和体内研究。我们的首要假设是，时钟蛋白Rev-Erba的细胞状态是 是免疫能力的关键决定因素，可以调节以改善脓毒症的结果。 我们特别假设Rev-Erba调节支持免疫的蛋白质机制， 单核吞噬细胞和B细胞的表型，并对有效的免疫应答至关重要， 微生物威胁 在目标1中，我们将研究蓝光和时钟蛋白的生理和细胞机制。 Rev-Erba调节单核细胞向脾和外周组织的募集，并分化为一种类型的单核细胞。 单核细胞高效清除细菌，使用KP肺炎模型。在目标2中，我们将探讨 蓝光和Rev-Erba调节B细胞PI 3 K-AKT-mTOR信号和肌动蛋白组装的机制 介导B细胞分化、活化、MHC II抗原呈递和抗体产生。因为这些 机制是代谢要求和ATP依赖性，我们将（目的3）确定的机制， 其中Rev-Erba调节线粒体动力学以支持氧化代谢， 脓毒症期间免疫细胞的表型。 光对健康和疾病的影响仍有待令人信服的定义。该提案将定义 生物钟蛋白通过其有益地改变宿主对急性炎症反应的生物学机制， 有感染力的侮辱我们将定义光的维度和最佳保护的时钟蛋白的状态 并在肺炎患者的研究中检查它们的生物学相关性和潜在的治疗价值。