Assessment of Inflammatory Responses and Novel Systemic Signals as Potential Screening Targets of Shift-Work Related Disruption.

评估炎症反应和新的系统信号作为轮班工作相关干扰的潜在筛选目标。

• 批准号: 10330410
• 负责人: Oscar Castanon-Cervantes
• 金额: $ 34.92万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330410
• 关键词: Anti-Inflammatory Agents; Award; Behavioral; Cardiovascular Diseases; Characteristics; Chronic; Circadian Dysregulation; Clinical; Complex; Data; Development; Diabetes Mellitus; Diet; Disease; Endotoxins; Energy Metabolism; Environment; Environmental Risk Factor; Event; Exposure to; Goals; Health; Hormones; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Lead; Light; Link; Lipopolysaccharides; Malignant Neoplasms; Measures; Mediator of activation protein; Melatonin; Minority Groups; Monitor; Occupational; Occupational Exposure; Pathology; Pathway interactions; Periodicity; Physical activity; Physiological; Pilot Projects; Plasma; Predisposition; Preventive; Prospective Studies; Public Health; Research; Risk; Risk Assessment; Risk Factors; Sampling; Screening procedure; Severities; Signal Transduction; Sleep; Sleep Deprivation; Stress; Testing; Time; Work; Workplace; career; circadian; defined contribution; diabetes risk; diagnostic tool; disorder risk; experience; health equity; improved; insight; monocyte; novel; occupational hazard; pre-clinical research; predicting response; response; screening; shift work; stroke risk; systemic inflammatory response; tool; translational study

ABSTRACT Shift workers represent nearly 30 % of the US workforce, and this occupational hazard conveys increased risk for multiple pathologies. Still, the specific mechanisms behind this increased risk of illness by shift workers as well as investigation of screening targets to identify susceptible individuals are scarcely known. Our preclinical research and initial translational studies provide insight into the basis of shift-work disease and show that markers of systemic inflammation appear to increase as a function of exposure-duration to shift work. However, when samples are challenged with bacterial endotoxin, we find that low-grade systemic inflammation does no warrant a heightened ex-vivo endotoxin response. As shift work exposure increases, the relationship between systemic inflammation and endotoxin responses weakens, suggesting a mismatch between discrete pro- and anti-inflammatory pathways during endotoxin challenge. Novel systemic signals in plasma samples from shift workers identify a potential mediator of shift-work related disruption of inflammation. These preliminary results illustrate how shift work impacts the complex interaction of events needed to initiate and control an efficient response to an inflammatory challenge and support the hypothesis that chronic dysregulation of inflammation is behind the increased risk of diabetes, cancer and cardiovascular disease in shift workers. In this application, we propose to conduct a cross-sectional prospective study of day workers and career shift workers exposed to temporally changing occupational environments. We will further develop and improve a profile of shift-work risk assessment which includes individual metrics of systemic inflammation, cardiovascular disease, stress, sleep/activity, diet composition, and circadian disruption. This assessment aims to quantify the state of low-grade systemic inflammation characteristic of shift work exposure as a potential predictor of the response of the immune system to a controlled, ex-vivo and in-vitro, endotoxin challenge. We aim to assess the potential mechanisms by which increased inflammation determine dysregulated activation and test the central hypothesis that the degree of low-grade systemic inflammation worsens with increased shift work exposure. Our primary goal is to understand how shift work exposure duration leads to the development of uncontrolled inflammation in career shift workers increasing disease risk. This work is of paramount importance because it could lead to early diagnostic tools that can help mitigate shift-work disease. On the long term, we seek to uncover the mechanistic links between shift work exposure and disease.

摘要 轮班工人占美国劳动力的近30%，这种职业危害传达了更大的风险 多种病理学。尽管如此，这背后的具体机制增加了轮班工人患病的风险， 以及对筛查目标进行调查以识别易感个体的情况鲜为人知。 我们的临床前研究和初步转化研究提供了深入了解轮班工作疾病的基础， 显示全身炎症标志物似乎随着轮班工作的持续时间而增加。 然而，当样品用细菌内毒素挑战时，我们发现， 并不能保证离体内毒素反应的增强。随着轮班工作的增加， 系统性炎症和内毒素反应之间的关系减弱，表明离散的促炎症反应和内毒素反应之间不匹配。 和抗炎途径。血浆样品中的新系统信号 轮班工作者确定了轮班工作相关的炎症破坏的潜在介质。这些初步 结果表明，轮班工作如何影响复杂的相互作用的事件需要启动和控制一个 有效的反应，炎症的挑战，并支持这一假设，慢性失调， 炎症是轮班工人患糖尿病、癌症和心血管疾病风险增加的原因。 在这项申请中，我们建议进行一项关于日工和职业转换的横断面前瞻性研究 工作环境随时间变化的工人。我们将进一步发展和完善 轮班工作风险评估概况，包括全身炎症、心血管 疾病、压力、睡眠/活动、饮食组成和昼夜节律紊乱。该评估旨在量化 轮班工作暴露的低度全身性炎症特征状态作为潜在的预测因子 免疫系统对受控的离体和体外内毒素挑战的反应。我们的目标是评估 增加的炎症决定失调的激活的潜在机制，并测试中枢神经系统的功能。 假设低度全身性炎症的程度与轮班工作暴露的增加有关。 我们的主要目标是了解轮班工作暴露时间如何导致不受控制的发展。 职业轮班工人的炎症增加了疾病风险。这项工作至关重要，因为它 可能导致早期诊断工具，可以帮助减轻轮班工作疾病。从长远来看，我们寻求发现 轮班工作暴露与疾病之间的机械联系。