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: 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
• 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

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.

昼夜节律在广泛的生理和行为过程中发挥着重要作用。在哺乳动物中,