Role of Circadian Clock in Lung Inflammation

摘要： 拟议的研究描述了一个为期4年的培训计划，以发展一个以研究为重点的学术 流感病毒诱发肺部炎症的机制。 候选人Shaon Sengupta是新生儿重症监护室（NICU）的主治医师。 费城儿童医院她通过从事密集的基础科学来扩展她的训练 Ruth L. Kirschstein国家研究服务奖（T32），并继续 由儿科系儿童健康研究职业发展奖（K12）支持。这项工作 将在加勒特·A的指导下进行。菲茨杰拉德医学博士昼夜节律领域的领导者 是前列腺素生物学的先驱他是系统系主任 佩雷尔曼医学院的药理学和转化治疗学，以及ITMAT主任 并且有着出色的指导记录 甲型流感病毒（Influenza A virus，IAV）感染是世界范围内引起肺部疾病和死亡的主要原因。 最近的临床研究表明，对流感疫苗的反应取决于一天中的时间， 接种了疫苗。此外，Sengupta博士已经生成了初步数据，证明了 肺感染IAV的可能性取决于动物暴露于IAV的时间。大多数昼夜变化的迹象， 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， IAV发病机制中的昼夜节律尚不清楚。拟议工作的目标是： 1.目的探讨IAV感染后免疫应答昼夜变化的机制。 2.为了验证昼夜节律钟是IAV诱导的肺组织昼夜变化的原因的假设， 伤害和死亡率， a.确定核心时钟基因Bmal1的缺失是否放大了严重性并废除了昼夜节律， IAV诱导的肺损伤的差异。 B.确定IAV诱导的昼夜节律控制的细胞机制 炎症这将通过研究骨髓细胞中Bmal1的缺失是否 （LysMCreBmal1-/-小鼠-先天免疫钟）或肺上皮（CCSPCreBmal1-/-小鼠） 导致放大的严重性和IAV时钟门控的丢失。 3.为了测试对IAV感染反应的昼夜节律控制的中断是否是IAV感染增加的基础， 病毒感染后气道高反应性（AHR）。 完成拟议的工作，预计将提供新的见解昼夜调节组件 决定IAV中宿主反应、病毒后AHR和肺部炎症。

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.