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: 10582781
• 负责人: MATTHEW Randall ROSENGART
• 金额: $ 37.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582781
• 关键词: Actins; Acute; Agonist; Antibody Formation; Antigen Presentation; Attention; Attenuated; Autonomic nervous system; B cell differentiation; B-Cell Development; B-Lymphocytes; Bacteria; Biological; Biology; Bone Marrow; Cell Respiration; Cells; Cellular biology; Clock protein; Complex; Cues; Data; Development; Dimensions; Disease; Evolution; Exposure to; Eye; FRAP1 gene; Gene Cluster; Genes; Health; Histocompatibility Antigens Class II; Hour; Human; Hypothalamic structure; Immune; Immune response; Immunity; Immunocompetence; Immunoglobulins; In Vitro; Individual; Infection; Infection Control; Inflammation; Inflammatory; Interferon Type I; Interferons; Kidney; Klebsiella pneumoniae; Leukocytes; Light; Liver; Mammalian Cell; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Mononuclear; Mus; Natural Immunity; Neuraxis; Ontology; Optics; Organ; Organism; Outcome; Pathway interactions; Patients; Peripheral; Phagocytes; Phenotype; Physiological; Physiology; Pineal gland; Pituitary Gland; Pneumonia; Population; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Reperfusion Injury; Research; Role; Sepsis; Signal Pathway; Signal Transduction; Spleen; Splenectomy; Stress; System; Therapeutic; Tissue Differentiation; Tissues; Travel; Work; adaptive immunity; blue light therapy; cholinergic; circadian; circadian biology; circadian pacemaker; fitness; immune function; improved outcome; in vivo; innovation; microbial; monocyte; mouse model; neurophysiology; organ injury; pathogen; programs; recruit; response; rev Protein; septic; single-cell RNA sequencing; suprachiasmatic nucleus; systemic inflammatory response; tissue injury

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组调节细胞生物学的核心生物钟蛋白 支持更复杂的器官生理学。中枢神经系统，被原理缠绕在一起 环境提示光，使这些外围细胞的时钟在整个生物体内同步，这 使寄主有机体能够预测和准备活动一天的压力(例如，代谢 要求、败血症威胁)。目前的证据，包括来自我们自己的研究项目的数据， 强调单个时钟蛋白对生理能力的深刻影响 有机体对压力做出反应。我们首先认识到，光的光谱是其影响的关键决定因素 在哺乳动物生物学上，短波长可见蓝色光谱有利于改变 脓毒症的生物学和转归。小鼠腹腔内脓毒症和肺炎克雷伯菌模型的建立 肺炎，败血症后暴露在蓝光下可以增强免疫能力，这一点得到了更有效的证明 清除脓毒症病灶中的细菌，减少细菌传播，并减弱全身 发炎。其机制涉及一条诱导时钟蛋白Rev-Erba的光-胆碱能途径 在脾和MJ的免疫组织中。REV-ERBA激动剂在体外同样增强两者的免疫功能 以及活体研究。我们的主要假设是时钟蛋白REV-ERBA的细胞状态是 是免疫能力的关键决定因素，可以被调节以改善脓毒症的结局。 我们特别假设REV-ERBA调节支持免疫的蛋白质机制 单核巨噬细胞和B细胞的表型，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 REV-ERBA调节单核细胞向脾和外周组织的募集并分化为一种 单核细胞清除细菌的效率很高，使用的是KP肺炎模型。在目标2中，我们将探索 蓝光和REV-ERBA调控B细胞PI3K-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抗原递呈和抗体产生。就像这些 机制是新陈代谢要求和依赖的，我们将(目标3)通过以下方式确定机制 其中REV-ERBA调节线粒体动力学以支持氧化代谢，从而 脓毒症时免疫细胞的表型。 光对健康和疾病的影响仍有待令人信服的定义。这项提案将界定 昼夜节律时钟蛋白有益地改变宿主对急性呼吸综合征的反应的生物学机制 有感染力的侮辱。我们将定义具有最佳保护作用的光的维度和时钟蛋白的状态 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。