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

基本信息

批准号：
10328924
负责人：
Erol Fikrig
金额：
$ 47.3万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-08 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328924
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 Data Dendritic Cells Diurnal Rhythm Elderly Enrollment Evolution Family member Feedback Gene Expression Gene Proteins 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 base 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 expression receptor function response sleep regulation suprachiasmatic nucleus transcription factor treatment response young adult

项目摘要

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.

昼夜节律在哺乳动物的各种生理和行为过程中发挥着至关重要的作用。光强度的变化和其他环境线索由主起搏器集成下丘脑的视交叉上核，通过以下方式带动多个外周生物钟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环中，而昼夜节律则在其中。哺乳动物通常与睡眠-觉醒、体温、心血管和代谢有关调节，昼夜节律也被报道用于免疫过程，包括每日 CD4 和 CD8 T 细胞等细胞群水平和细胞因子表达的波动。首先报道了Toll样受体（TLR）-9，先天免疫的模式识别受体之一系统，显示表达和功能的日常变化，这些变化受环昼夜节律时钟成分的调节我们发现，TLR9 依赖性小鼠对 TLR9 佐剂疫苗的反应和疾病严重程度都存在差异。脓毒症模型取决于疫苗接种或脓毒症诱导的时间，这意味着昼夜节律控制为我们的初步数据还表明了一种新的先天免疫调节机制。人类的 TLR 反应也有多项证据表明，昼夜节律也会受到干扰。人类和小鼠的衰老，以及缺乏“时钟”基因的基因敲除小鼠会出现与衰老相关的表型然而，关于衰老是否影响昼夜节律变化仍然存在知识空白。我们发现，在小鼠和人类的 TLR 反应中，这种差异都会随着年龄的增长而减弱。人类和小鼠，并聚集了具有人类和小鼠专业知识的跨学科研究小组我们将重点关注小鼠免疫学、睡眠研究、时间生物学和衰老研究来检验这一假设。评估与病毒感染反应相关的 TLR（小鼠中的 TLR3, 7, 9 和人类中的 TLR3, 7-9）我们已发表和未发表的小鼠数据表明昼夜节律变化，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，以及体内和体内的表达 TLR依赖性细胞因子产生、共刺激蛋白表达和反应的体外昼夜节律变化年轻和老年（20-22 个月大）小鼠以及年轻（21-30 岁）和老年（≥ 65 年）人类。拟议的人体研究将整合免疫学数据与生理参数。时间生物学中的昼夜节律循环标准，例如多导睡眠图以及皮质醇和核心的测量昼夜节律先天免疫功能的研究可能会在考虑方面取得新突破。这些见解会影响感染的易感性或结果的时间变化，或对治疗的反应。对老年人有重大影响，众所周知，老年人的发病率和死亡率增加传染病和疫苗接种反应受损。