Role of Circadian Clock in Lung Inflammation

昼夜节律钟在肺部炎症中的作用

• 批准号: 9314903
• 负责人: Shaon Sengupta
• 金额: $ 15.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314903
• 关键词: ARNTL gene; Acute; Alveolar Macrophages; Animals; Antiviral Agents; Area; Asthma; Basic Science; Binding; Biological Assay; Biological Process; Biology; Bronchoalveolar Lavage; Cell physiology; Cells; Cessation of life; Child health care; Chronic; Chronic Obstructive Airway Disease; Circadian Rhythms; Clinical; Clinical Research; Data; Department chair; Development Plans; Doctor of Medicine; Dose; E-Box Elements; Environment; Epithelium; Feedback; Flow Cytometry; Genes; Genetic Models; Genetic Transcription; Goals; Harvest; Health; Histology; Hormones; Hospitalization; Hour; Immune; Immune response; Immune system; Inflammation; Inflammatory; Influenza; Influenza A virus; K-Series Research Career Programs; Knockout Mice; Leukocytes; Literature; Lung; Lung Inflammation; Measures; Mediating; Mentors; Mentorship; Molecular; Molecular Profiling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myeloid Cells; National Research Service Awards; Neonatal Intensive Care Units; Organism; PTPRC gene; Pathway Analysis; Pathway interactions; Peak Expiratory Flow Rate; Pediatric Hospitals; Periodicity; Peripheral; Pharmaceutical Preparations; Pharmacology; Philadelphia; Promoter Regions; Prostaglandins; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Inflammation; Regulation; Research; Research Support; Respiration Disorders; Respiratory Signs and Symptoms; Role; SECTM1 gene; Severities; Signs and Symptoms; System; Techniques; Testing; Therapeutic; Time; Tissues; Training; Treatment Efficacy; Vaccines; Variant; Viral; Viral Respiratory Tract Infection; Virus Diseases; Virus Replication; Work; adaptive immune response; airway hyperresponsiveness; base; chemokine; circadian pacemaker; cytokine; experience; experimental study; immune function; improved; influenza virus vaccine; influenzavirus; insight; lung injury; medical schools; mortality; novel; novel therapeutic intervention; pediatric department; postnatal; public health priorities; pulmonary function; response; transcriptome sequencing; virus pathogenesis

Abstract: The proposed study describes a 4-year training plan for the development of an academic with a research focus on the mechanisms that underlie influenza virus induced pulmonary inflammation. The candidate, Shaon Sengupta is an attending neonatologist at the Neonatal Intensive Care Unit (NICU) of the Children's Hospital of Philadelphia. She has extended her training by engaging in intensive basic science research supported by the Ruth L. Kirschstein National Research Service Award (T32), and continues to be supported by the Department of Pediatrics Child Health Research Career Development Award (K12). This work will be carried out under the mentorship of Garret A. FitzGerald, M.D. a leader in the fields of circadian rhythms of peripheral clocks and a pioneer in prostanoid biology. He is the Chair of the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine, and the director of ITMAT and has an outstanding track record for mentorship. Influenza A virus (IAV) infection is a major infectious cause of pulmonary morbidity and mortality in the world. Recent clinical studies suggest that the response to influenza vaccine depends on the time of day at which the vaccine was administered. Further, Dr. Sengupta has generated preliminary data, proving that the response of the lung to IAV depends on the time at which the animal was exposed to IAV. Most diurnal variations in signs, symptoms or response to therapy are generated by the influence of the circadian system. However, the role of circadian rhythms in IAV pathogenesis is not known. The goals of the proposed work are: 1. To determine the mechanisms underlying the diurnal variation in the immune response to IAV infection. 2. To test the hypothesis that the circadian clock is responsible for the diurnal variation in IAV-induced lung injury and mortality, by a. Determining if the loss of core clock gene Bmal1 amplifies the severity and abrogates the diurnal difference in IAV induced lung injury. b. Determining the cellular mechanisms underlying the circadian control of IAV induced inflammation. This will be achieved by investigating whether the loss Bmal1 in myeloid cells (LysMCreBmal1-/- mice-- innate immune clock) or in the lung epithelium (CCSPCreBmal1-/- mice) leads to the amplified severity and loss of clock gating to IAV. 3. To test if a disruption of the circadian control over the response to IAV infection underlies the increase in post-viral airway hyper-reactivity (AHR). Completion of the proposed work is expected to provide novel insights into the circadian regulatory components that determine host response, post viral AHR and lung inflammation in IAV.

抽象的： 拟议的研究描述了一个针对以研究为重点的学者发展的 4 年培训计划 流感病毒引起肺部炎症的机制。 候选人 Shaon Sengupta 是新生儿重症监护病房 (NICU) 的一名新生儿主治医师。 费城儿童医院。她通过从事强化基础科学来扩展她的培训 该研究由 Ruth L. Kirschstein 国家研究服务奖 (T32) 支持，并继续 得到儿科儿童健康研究职业发展奖（K12）的支持。这部作品 将在昼夜节律领域的领导者、医学博士加勒特·A·菲茨杰拉德 (Garret A. FitzGerald) 的指导下进行 外周时钟的研究者和前列腺素生物学的先驱。他是系统系系主任 佩雷尔曼医学院药理学和转化治疗学、ITMAT 主任 并在指导方面拥有出色的记录。 甲型流感病毒（IAV）感染是世界范围内肺部发病和死亡的主要感染原因。 最近的临床研究表明，对流感疫苗的反应取决于一天中接种疫苗的时间。 注射了疫苗。此外，Sengupta 博士还生成了初步数据，证明了 肺部对 IAV 的影响取决于动物接触 IAV 的时间。大多数迹象的日变化， 症状或对治疗的反应是由昼夜节律系统的影响产生的。然而，角色 昼夜节律在 IAV 发病机制中的作用尚不清楚。拟议工作的目标是： 1. 确定 IAV 感染免疫反应昼夜变化的机制。 2. 检验昼夜节律钟导致 IAV 引起的肺部昼夜变化的假设 伤害和死亡，由 一个。确定核心时钟基因 Bmal1 的丢失是否会加剧严重程度并消除昼夜节律 IAV 引起的肺损伤的差异。 b.确定 IAV 诱导的昼夜节律控制的细胞机制 炎。这将通过研究骨髓细胞中的 Bmal1 是否丢失来实现 （LysMCreBmal1-/- 小鼠 - 先天免疫时钟）或肺上皮细胞（CCSPCreBmal1-/- 小鼠） 导致 IAV 时钟门控的严重性放大和丢失。 3. 测试对 IAV 感染反应的昼夜节律控制的破坏是否是导致 IAV 感染增加的原因 病毒后气道高反应性（AHR）。 拟议工作的完成预计将为昼夜节律调节成分提供新的见解 决定 IAV 中宿主反应、病毒后 AHR 和肺部炎症。