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.

抽象的 每个哺乳动物细胞中是调节细胞生物学的昼夜节律蛋白的核心集 支持更复杂的器官生理。中枢神经系统，由原理纳 环境提示 - 光线，使整个生物体中的这些外围细胞“时钟”同步 使宿主有机体能够预测并为活性日的压力做准备（例如，代谢 需求，化粪池威胁）。当前的证据，包括来自我们自己的研究计划的数据， 强调各个时钟蛋白对生理能力的深远影响 有机体对压力做出反应。我们首先确定光谱是其影响的关键决定者 关于哺乳动物的生物学，短波长可见的蓝光谱可改进 败血症的生物学和结果。在腹腔内败血症和肺炎克雷伯氏菌（KP）的鼠模型中 肺炎，败血症增强的免疫能力后暴露于蓝光，可有效地证明 从化粪池焦点中清除细菌，细菌传播减少并衰减全身性 炎。该机制涉及诱导时钟蛋白Rev-Erba的视觉胆碱能途径 在脾脏和MJ的免疫动物中。 Rev-Erba激动剂类似地增强了两者的免疫功能 和体内研究。我们的总体假设是，时钟蛋白Rev-erba的细胞状态是 免疫能力的关键决定因素，可以调节以改善败血症的结果。 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，对于有效的免疫反应至关重要 微生物威胁。 在AIM 1中，我们将研究蓝光和时钟蛋白的生理和细胞机制 Rev-erba调节单核细胞募集到脾脏和外围组织，并分化为一种类型 单核细胞使用KP肺炎模型在细菌清除率上高效。在AIM 2中，我们将探索 蓝光和Rev-erba调节B细胞PI3K-AKT-MTOR信号和肌动蛋白组件的机制 介导B细胞分化，激活，MHC II抗原表现和抗体产生。这样 机制是代谢要求的，并且依赖于ATP，我们将（AIM 3）确定机制 Rev-erba调节线粒体动力学以支持氧化代谢，从而 败血症期间免疫细胞的表型。 关于健康和疾病的灯光的影响仍然有令人信服的定义。该建议将定义 昼夜节律时钟蛋白有益地改变宿主对急性的反应的生物学机制 传染性的侮辱。我们将定义最佳保护的光和时钟蛋白的状态的尺寸 并检查其生物学相关性和潜在的治疗价值在肺炎患者的研究中。