Aging of tissue-specific clocks in the immune system of Drosophila

果蝇免疫系统中组织特异性时钟的老化

• 批准号: 8720663
• 负责人: Michele M Shirasu-Hiza
• 金额: $ 27.83万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720663
• 关键词: Accounting; Age; Aging; Aging-Related Process; Animal Model; Animals; Biological Models; Biological Process; Biology; Birds; Blood Cells; Brain; Caloric Restriction; Cause of Death; Cell physiology; Cells; Circadian Dysregulation; Circadian Rhythms; Communicable Diseases; Data; Defect; Dominant-Negative Mutation; Drosophila genus; Drug Metabolic Detoxication; Elderly; Exhibits; Fishes; Fluorescence; Functional disorder; Gene Expression; Genes; Genetic; Health; Hour; Human; Immune; Immune response; Immune system; Immunity; Immunofluorescence Immunologic; Individual; Infection; Inflammatory; Inflammatory Response; Influenza; Ingestion; Learning; Length; Link; Longevity; Mammals; Metabolism; Microbe; Modeling; Molecular; Natural Immunity; Nobel Prize; Nuclear; Organism; Pathology; Peripheral; Phagocytes; Phagocytosis; Physiological; Physiology; Pneumonia; Predisposition; Regulation; Reporter; Septicemia; System; Testing; Time; Tissues; Vertebrates; age effect; age related; aging brain; circadian pacemaker; fly; follow-up; genetic manipulation; human old age (65+); immune phagocytosis; immunosenescence; in vivo; insight; macrophage; middle age; mutant; prevent; receptor; research study; senescence; tool

DESCRIPTION (provided by applicant): Aging of immune system function, or immunosenescence, is poorly understood but is thought to underlie increased susceptibility to infection of the elderly. A major hallmark of immunosenescence is dysfunction of macrophages, a type of immune blood cell. Macrophages in elderly people exhibit decreased number and phagocytic activity (the ingestion of microbes), as well as abnormal inflammatory responses, which impact inflammatory pathologies of aging. The cause(s) of macrophage senescence remains unknown. Another classic sign of aging in animals from flies to humans is loss of circadian regulation. This proposal tests the hypothesis that aging causes defects in the circadian clock located in immune blood cells, which in turn causes defects in their cellular function and contributes to increased susceptibility to infection. We developed a model system to study circadian regulation of primitive macrophages in Drosophila, using genetic and immunological tools unavailable in other systems. We found that immunity against infection is circadian- regulated. Specifically, phagocytosis by macrophages (or phagocytes) is circadian-regulated and this circadian regulation has significant effects on survival of infection. Our current data show that aging of Drosophila causes dramatic susceptibility to infection-specifically, old flies lose circadian regulation of phagocytosis. Because we and others find that the clock in phagocytes regulates their function, these data suggest a model: aging causes circadian dysregulation in phagocytes, which causes defects in phagocytosis and increased susceptibility to infection. To test this model, we will: 1. Test the hypothesis that the clock in phagocytes undergoes aging-related senescence and identify the underlying molecular mechanism. 2. Determine the effect of the aging phagocyte clock on gene expression and cellular function. 3. Investigate the causal relationships between circadian healthspan, immunosenescence, and lifespan. Thus the proposed experiments will analyze the aging of circadian regulation of immune system function on molecular, cellular, and organismal levels. Phagocytosis is an ancient and crucial part of every animal's innate immune system, including humans. Because of the high evolutionary conservation of both innate immunity and circadian biology, defining these molecular mechanisms in Drosophila will provide insight into ways to ameliorate or prevent aging of human innate immune system function.

描述（由申请人提供）：免疫系统功能老化，或免疫衰老，知之甚少，但被认为是老年人对感染易感性增加的基础。免疫衰老的一个主要标志是巨噬细胞（一种免疫血细胞）功能障碍。老年人巨噬细胞数量和吞噬活性（微生物摄取）下降，炎症反应异常，影响衰老的炎症病理。巨噬细胞衰老的原因尚不清楚。从苍蝇到人类，动物衰老的另一个典型标志是昼夜节律调节的丧失。这一提议验证了一个假设，即衰老会导致免疫血细胞中的生物钟出现缺陷，进而导致其细胞功能出现缺陷，并导致对感染的易感性增加。我们开发了一个模型系统来研究果蝇原始巨噬细胞的昼夜节律调节，使用了其他系统中不可用的遗传和免疫学工具。我们发现对感染的免疫是受昼夜节律调节的。具体来说，巨噬细胞（或吞噬细胞）的吞噬是受昼夜节律调节的，这种昼夜节律调节对感染的存活有显著影响。我们目前的数据表明，果蝇的衰老会导致对感染的显著易感性——具体来说，老年果蝇失去了吞噬的昼夜节律调节。因为我们和其他人发现吞噬细胞中的时钟调节它们的功能，这些数据提出了一个模型：衰老导致吞噬细胞的昼夜节律失调，从而导致吞噬缺陷和对感染的易感性增加。为了测试这个模型，我们将：1。测试吞噬细胞中的时钟经历与衰老相关的衰老的假设，并确定潜在的分子机制。2. 确定老化的吞噬细胞时钟对基因表达和细胞功能的影响。3. 研究昼夜健康期、免疫衰老和寿命之间的因果关系。因此，提出的实验将从分子、细胞和有机体水平上分析免疫系统功能的昼夜节律调节的衰老。吞噬作用是包括人类在内的所有动物先天免疫系统中一个古老而重要的组成部分。由于先天免疫和昼夜节律生物学的高度进化守恒，在果蝇中定义这些分子机制将为改善或预防人类先天免疫系统功能衰老的方法提供见解。