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 每个哺乳动物细胞内都有一组核心的生物钟蛋白，可调节细胞生物学 支持更复杂的器官生理学。中枢神经系统，受原理牵引 环境线索——光，使整个生物体的外围细胞“时钟”同步， 使宿主有机体能够预测并为活跃一天的压力做好准备（例如，代谢 要求、化粪池威胁）。目前的证据，包括来自我们自己的研究计划的数据， 强调个体时钟蛋白对生理能力的深远影响 有机体对压力做出反应。我们首先发现光谱是其效果的关键决定因素 对哺乳动物生物学的影响，短波长可见蓝色光谱有利于改变 脓毒症的生物学和结果。在腹内败血症和肺炎克雷伯菌 (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，证据更有效 清除脓毒病灶中的细菌，减少细菌传播，并减弱全身感染 炎。该机制涉及诱导时钟蛋白 Rev-Erba 的视胆碱能通路 在脾脏和 Mj 的免疫组织中。 Rev-Erba 激动剂在体外同样能增强免疫功能 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 免疫能力的关键决定因素，可以进行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，对于有效的免疫反应至关重要 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 调节单核细胞向脾脏和外周组织的募集并分化为一种 使用 KP 肺炎模型，单核细胞能够高效清除细菌。在目标 2 中，我们将探索 蓝光和 Rev-Erba 调节 B 细胞 PI3K-AKT-mTOR 信号传导和肌动蛋白组装的机制 介导 B 细胞分化、激活、MHC II 抗原呈递和抗体产生。正如这些 机制需要代谢且依赖于 ATP，我们将（目标 3）通过以下方式确定机制： Rev-Erba 调节线粒体动力学以支持氧化代谢，从而 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地定义。该提案将定义 生物钟蛋白通过生物机制有益地改变宿主对急性应激的反应 传染性的侮辱。我们将定义光的维度和具有最佳保护作用的时钟蛋白的状态 并检查它们在肺炎患者研究中的生物学相关性和潜在治疗价值。