Circadian Rhythms and Innate Immune Response in Aging

衰老过程中的昼夜节律和先天免疫反应

• 批准号: 10552019
• 负责人: Erol Fikrig
• 金额: $ 46.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-08 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552019
• 关键词: ARNTL gene; Acute; Adjuvant; Adult; Affect; Age; Age Months; Age Years; Aging; Antibody Response; Antigen-Presenting Cells; Attenuated; B-Lymphocytes; Bacterial Infections; Behavioral; Biological Process; Blood specimen; Body Temperature; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; Cardiovascular system; Cells; Chronobiology; Circadian Rhythms; Clinical; Clinical Investigator; Clock protein; Communicable Diseases; Cues; Cultured Cells; Cytometry; Darkness; Data; Dendritic Cells; Diurnal Rhythm; Elderly; Enrollment; Evolution; Exclusion; Family member; Feedback; Gene Expression; Generations; Genes; Genetic Transcription; Hormonal; Host Defense; Hour; Human; Hydrocortisone; Hypothalamic structure; Immune; Immune response; Immune system; Immunologic Receptors; Immunologics; Immunology; Impairment; In Vitro; Infection; Infectious Agent; Inflammatory; Innate Immune Response; Innate Immune System; Knockout Mice; Knowledge; Light; Link; Lymphocyte; Mammals; Measurement; Medicine; Metabolic; Modeling; Molecular; Morbidity - disease rate; Mus; Neurosecretory Systems; Organ; Outcome; Outpatients; Pacemakers; Pattern; Pattern recognition receptor; Periodicity; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Physiological Processes; Play; Polysomnography; Population; Post-Translational Protein Processing; Predisposition; Premature aging syndrome; Prevalence; Process; Production; Proteins; Publishing; Recording of previous events; Regulation; Reporting; Research; Research Personnel; Rodent; Role; Sepsis; Series; Serum; Severity of illness; Shock; Sleep; Sleep Disorders; Sleep disturbances; Streptococcus pneumoniae; Sumoylation Pathway; System; TLR3 gene; TLR7 gene; TLR9 gene; Temperature; Testing; Time; Toll-like receptors; Translations; Ubiquitination; Vaccination; Vaccines; Variant; Virus; Virus Diseases; Wrist; actigraphy; adaptive immune response; age effect; aged; circadian; circadian pacemaker; circadian regulation; cytokine; experience; experimental study; immunoregulation; in vivo; innate immune function; innate immune mechanisms; insight; interest; light intensity; monocyte; mortality; novel; pathogen; protein expression; receptor; receptor expression; receptor function; response; sleep regulation; suprachiasmatic nucleus; transcription factor; treatment response; young adult

Circadian rhythms play crucial roles in a wide range of physiologic and behavioral processes. In mammals, variations in light intensity and other environmental cues are integrated by a master pacemaker in the suprachiasmatic nuclei of the hypothalamus, which entrains multiple peripheral circadian clocks via neuroendocrine mechanisms. The clock at the molecular level consists of a network of transcription factors organized in a series of highly conserved transcription-translation feedback loops. While circadian rhythms in mammals are typically associated with sleep-wake, body temperature, cardiovascular, and metabolic regulation, circadian periodicity has also been reported for immunologic processes as well, including daily oscillation in levels of cell populations such as CD4 and CD8 T cells and cytokine expression. We were the first to report that Toll-like Receptor (TLR)-9, one of the pattern recognition receptors of the innate immune system, shows daily variation in expression and function that is modulated by circadian clock components in mice. We found that both response to a TLR9 adjuvanted vaccine and disease severity in a TLR9-dependent sepsis model were dependent on the timing of vaccination or sepsis induction, implicating circadian control as a novel mechanism of innate immune regulation. Our preliminary data also suggests circadian variation of TLR responses in humans as well. Several lines of evidence suggest that circadian rhythms are disrupted by aging in humans and mice, and knockout mice deficient in “clock” genes develop phenotypes associated with premature aging. However, there remains a knowledge gap as to whether aging influences circadian variation in TLR responses in mice and humans. We hypothesize that such variation will be attenuated by aging in both humans and mice, and have assembled in interdisciplinary group of investigators with expertise in human and mouse immunology, sleep research, chronobiology and aging research to test this hypothesis. We will focus on evaluating TLRs associated with response to viral infection (TLR3, 7, 9 in mice and TLR3, 7-9 in humans) for which our published and unpublished data in mice suggest circadian variation. We will assess circadian TLR gene expression in purified populations of B cells, monocytes, and dendritic cells, as well as in vivo and in vitro circadian variation in TLR-dependent cytokine production, costimulatory protein expression, and response to viral infection in young and aged (20-22 months of age) mice and young (21-30 years) and older (≥ 65 years) humans. The proposed human studies will integrate immunologic data with physiologic parameters of circadian cycling standard in chronobiology, such as polysomnography, and measurements of cortisol and core body temperature. The study of circadian innate immune function is likely to break new ground in considering temporal variation in susceptibility or outcomes of infection, or in response to treatment. These insights would have substantial impact in older adults, who are known to have increased morbidity and mortality from infectious diseases and impaired responses to vaccination.

昼夜节律在许多生理和行为过程中起着至关重要的作用。在哺乳动物身上， 光强度的变化和其他环境信号由主起搏器在 下丘脑的视交叉上核，它通过 神经内分泌机制。分子水平的时钟由转录因子网络组成 组织在一系列高度保守的转录-翻译反馈循环中。而人体的昼夜节律 哺乳动物通常与睡眠、体温、心血管和新陈代谢有关。 此外，还报告了免疫过程的昼夜节律，包括每日 CD_4、CD_8、T细胞及细胞因子表达水平的波动。我们是 首次报道先天免疫的模式识别受体之一Toll样受体(TLR)-9 系统，显示表达和功能的每日变化，这是由生物钟成分调节的 老鼠。我们发现，在依赖TLR9的患者中，对TLR9佐剂疫苗的反应和疾病严重性都是如此 脓毒症模型依赖于接种疫苗或诱导脓毒症的时间，这意味着昼夜节律控制 一种新的天然免疫调节机制。我们的初步数据还表明， 人类对TLR的反应也是如此。有几条证据表明，昼夜节律被 人类和小鼠的衰老，以及“时钟”基因缺陷的基因敲除小鼠出现与以下相关的表型 过早衰老。然而，关于衰老是否会影响昼夜节律的变化，仍然存在一个知识空白。 在小鼠和人类的TLR反应中。我们假设，这种差异将随着年龄的增长而减弱。 人类和老鼠，并聚集在跨学科的研究小组，具有人类和 老鼠免疫学、睡眠研究、时间生物学和衰老研究来验证这一假说。我们将专注于 评估与病毒感染反应相关的TLR(小鼠TLR3、7、9和人类TLR3、7-9) 为此，我们在老鼠身上发表和未发表的数据表明了昼夜节律的变化。我们将评估昼夜节律 TLR基因在纯化的B细胞、单核细胞和树突状细胞群体中的表达，以及在体内和在 依赖TLR的细胞因子产生、共刺激蛋白表达和反应的体外昼夜节律变化 对年轻和老年(20-22月龄)小鼠和年轻(21-30岁)和老年(≥65)小鼠的病毒感染 几年)人类。拟议的人体研究将结合免疫学数据和生理参数。 时间生物学中的昼夜循环标准，如多导睡眠图和皮质醇和核心的测量 体温。对昼夜节律先天免疫功能的研究可能在考虑以下问题方面开辟新天地 感染易感性或结果的时间变化，或对治疗的反应。这些洞察力将 对老年人有重大影响，众所周知，老年人的发病率和死亡率 传染病和疫苗接种反应受损。