Novel mechanisms of immunological priming after circadian disruption

 描述（由申请人提供）：轮班工人占美国工作人口的近20%，并且表现出几种癌症，肥胖，糖尿病，中风和循环系统疾病的高发病率。更好地了解机械因素，有助于增加发病率在轮班工人之前，这些工作时间表的相关风险可以减少。在小鼠中模拟轮班工作，称为环境昼夜节律破坏（ECD），导致睡眠不足，加速死亡，先天免疫功能失调。暴露于ECD的小鼠表现出对细菌内毒素的病理性严重炎症反应和缺血性中风后梗死面积增加。我们的初步工作帮助我们建立了一个假设，即ECD破坏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。我们证实，由于通过受体酪氨酸激酶的TAM家族的足够信号传导的损失，这种免疫抑制在炎症激发期间特异性地减缓抗炎信号传导，导致不受控制的促炎细胞因子释放和病理学。在这项资助中，我们将使用新开发的体外ECD范式研究ECD免疫学后果的机制基础，为将我们的工作转化为暴露于实验室模拟和真实世界轮班工作的人类受试者奠定基础。这项研究工作的长期目标是开发筛查工具和预防性医学治疗，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.