Novel mechanisms of immunological priming after circadian disruption

 描述(由申请人提供)：倒班工人占美国工作人口的近20%，表现出几种癌症、肥胖症、糖尿病、中风和循环系统疾病的高发病率。在减少与这些工作时间表相关的风险之前，需要更好地了解导致轮班工人发病率增加的机械性因素。小鼠的模拟轮班工作，被称为环境昼夜节律紊乱(ECD)，会导致失眠，加速死亡，并扰乱天然免疫功能。ECD暴露的小鼠表现出对细菌内毒素的严重炎症反应，并在缺血性中风后增加梗塞面积。我们的初步工作帮助我们建立了一个假说，即ECD扰乱了免疫细胞的分子生物钟，并产生了一种新的免疫抑制形式。我们假设，这种免疫抑制在炎症刺激过程中特异性地减缓了抗炎信号，这是由于失去了通过受体酪氨酸激酶家族的足够信号，导致了不受控制的促炎细胞因子的释放和病理。在这笔赠款中，我们将使用新开发的体外ECD范例来研究ECD免疫学后果的机制基础，为将我们的工作翻译到暴露在实验室模拟和真实世界轮班工作中的人类受试者奠定基础。这项研究的长期目标是开发筛查工具和预防性医疗方法，以减轻与导致昼夜节律紊乱的工作时间表相关的不良健康后果。

 DESCRIPTION (provided by applicant): Shift workers comprise nearly 20% of the US working population, and exhibit disparately high rates of several cancers, obesity, diabetes, stroke, and circulatory disease. A better understanding of the mechanistic factors contributing to increased morbidity in shift workers is needed before the risks associated with these work schedules can be reduced. Simulated rotating shift work in mice, termed Environmental Circadian Disruption (ECD), leads to sleep loss, accelerates death, and dysregulates innate immune function. ECD-exposed mice exhibit pathologically severe inflammatory responses to bacterial endotoxin and increased infarct size following ischemic stroke. Our preliminary work has helped us establish a hypothesis that ECD disrupts the immune cell molecular circadian clock and produces a novel form of immunosuppression. We posit that this immunosuppression specifically slows anti-inflammatory signaling during an inflammatory challenge due to loss of adequate signaling through the TAM family of receptor tyrosine kinases, resulting in uncontrolled pro- inflammatory cytokine release and pathology. In this grant we will investigate the mechanistic underpinnings of the immunological consequences of ECD using newly developed in vitro ECD paradigms, laying the groundwork for translation of our work to human subjects exposed to laboratory-simulated and real-world shift work. The long term goal of this research effort is to develop screening tools and preventative medical treatments that may mitigate the adverse health consequences associated with work schedules that cause circadian disruption.