Circadian regulation of physiological functions

生理功能的昼夜调节

• 批准号: 10398025
• 负责人: Michele M Shirasu-Hiza
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398025
• 关键词: Aging; Alzheimer' s Disease; Animal Model; Bacteria; Bacterial Infections; Behavior; Biological Process; Bipolar Disorder; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Defect; Diabetes Mellitus; Disease; Disease Progression; Disease model; Drosophila genus; Epilepsy; Fragile X Syndrome; Health; Hour; Human; Huntington Disease; Immune; Infection; Inflammation; Jet Lag Syndrome; Lead; Metabolism; Modeling; Molecular; Mus; Natural Immunity; Neurologic; Obesity; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Phagocytes; Physiological; Physiology; Predisposition; Process; Role; Schizophrenia; Sleep; Sleep Deprivation; autism spectrum disorder; circadian; circadian regulation; human disease; malignant breast neoplasm; nervous system disorder; shift work; therapeutic target

PROJECT SUMMARY Circadian regulation refers to daily, 24-hour oscillations in biological functions and is a universal, evolutionarily conserved feature from bacteria to humans. Proper circadian regulation is important for human health, as chronic disruption of circadian regulation due to jetlag or night shift work is associated with multiple defects in metabolism, innate immunity, and sleep. These defects include susceptibility to infection, inflammation, obesity, and diabetes. Many diseases also cause loss of circadian regulation, including bacterial infection and many neurological diseases, such as autism and Parkinson’s disease. Despite the profound effects of circadian regulation on human health and physiology, it remains unclear how loss of circadian regulation contributes to the progression of these diseases. That is, a major gap in the field is the identification of specific circadian- regulated pathways that contribute to the pathogenesis of different diseases. My lab uses genetically tractable model organisms (fruit flies and mice) to investigate how disruption of circadian-regulated functions and behaviors contribute to the pathogenesis of bacterial infection and neurological disease models. This proposal focuses on investigating: 1) the role of metabolism in survival of bacterial infection; 2) the role of phagocytic innate immune cells in neurological defects associated with models of Fragile X syndrome, a human disease that causes both circadian dysregulation and autism; and 3) the role of sleep in defense against oxidative stress and the Drosophila model of Parkinson’s disease, which causes circadian dysregulation and sleep loss. These studies of circadian-regulated processes in the context of diseases that lead to circadian dysregulation will help to elucidate the cellular and molecular mechanisms underlying these diseases and identify new potential therapeutic targets

项目摘要 昼夜节律调节是指生物功能中每天24小时的振荡，是一种普遍的，进化上的 从细菌到人类的保守特征。适当的昼夜节律调节对于人类健康是重要的，因为慢性 由于时差或夜班工作引起的昼夜节律调节的中断与以下多种缺陷有关： 新陈代谢、先天免疫和睡眠。这些缺陷包括对感染、炎症、肥胖的易感性， 和糖尿病许多疾病也会导致昼夜节律调节的丧失，包括细菌感染和许多 神经系统疾病，如自闭症和帕金森病。尽管昼夜节律的影响深远， 调节对人类健康和生理的影响，目前尚不清楚昼夜节律调节的丧失如何有助于 这些疾病的发展。也就是说，该领域的一个主要空白是识别特定的昼夜节律- 调节途径，有助于不同疾病的发病机制。 我的实验室使用遗传学上易于处理的模式生物（果蝇和小鼠）来研究如何破坏 昼夜节律调节的功能和行为有助于细菌感染和神经系统疾病的发病机制。 疾病模型本研究的重点是：1）代谢在细菌存活中的作用 感染; 2）吞噬性先天免疫细胞在与脆性免疫缺陷模型相关的神经缺陷中的作用 X综合征，一种导致昼夜节律失调和自闭症的人类疾病;以及3）睡眠在 防御氧化应激和帕金森病的果蝇模型，这导致昼夜节律 调节失调和睡眠不足。这些关于疾病背景下昼夜节律调节过程的研究， 导致昼夜节律失调将有助于阐明这些潜在的细胞和分子机制 疾病并确定新的潜在治疗靶点