(CIRCADIAN) Circadian Disruption as Mediator of Cardiometabolic Risk in Air Pollution

摘要 颗粒物空气污染(PM2.5)是全球最大的环境风险因素，对环境的影响更大 全球死亡率比艾滋病、疟疾、结核病和战争/饥荒加起来还要多。与之相关的健康风险 PM2.5的主要原因是心血管(CV)原因，数据支持对公共健康的重大影响 由于2型糖尿病等疾病。在我们研究计划取得重大成功的基础上，我们在 这在很大程度上为我们理解PM2.5诱导的机制提供了基础基础 心脏代谢性疾病，我们提出了一个翻译研究的创新框架。我们的新数据 通过表观遗传学在PM2.5暴露和昼夜节律(CR)紊乱之间提供引人注目的联系 重新编程，导致代谢功能障碍和胰岛素抵抗。根据NIEHS 翻译研究框架，我们提出了一个雄心勃勃的计划，包括在8年内实现3个目标，将 包含涉及环境PM2.5集中暴露(动物)和人类的协调研究 由基因组结果预测和支持的跨环境暴露谱的干预试验 广泛关联和孟德尔随机化方法，将确定空气污染的中介路径 简历风险。利用正在进行的使用个性化策略减少空气污染的转化性临床试验 通过一项涉及缓解空气污染(ITS-MY-AIR)的新研究， 我们将评估暴露减少对CR中断/睡眠和代谢终点的影响。总而言之， 该项目的结果将有助于揭示空气污染及其对心脏代谢率和心脏代谢的影响 并提供关于个人干预策略的保护效果的有影响力的数据，这些策略加在一起可能 改变公共卫生政策。

ABSTRACT Particulate matter air pollution <2.5µm (PM2.5) is the leading environmental risk factor globally, contributing more to global mortality than AIDS, malaria, tuberculosis and wars/famines combined. The health risks associated with PM2.5 are predominantly from cardiovascular (CV) causes, with data supporting a major public health impact due to disorders such as type 2 diabetes. Building on the substantial successes of our research program, that in large part have provided the foundational basis for our understanding of mechanisms of PM2.5-induced cardiometabolic disorders, we propose an innovative framework of translational investigations. Our new data provide compelling links between PM2.5 exposure and circadian rhythm (CR) disruption through epigenetic reprogramming, resulting in metabolic dysfunction and insulin resistance. In accordance with the NIEHS Translational Research Framework, we propose an ambitious plan encompassing 3 goals over 8 years that will encompass harmonized studies involving concentrated ambient PM2.5 exposures (animal) and human intervention trials across the ambient exposure spectrum, predicated and supported by results from genome wide association and mendelian randomization approaches, that will identify pathways of air pollution mediated CV risk. Leveraging on-going translational clinical trials of air pollution reduction using personalized strategies in vulnerable populations in Beijing, and through one new study involving mitigation of air pollution (ITS-MY-AIR), we will evaluate the impact of exposure reduction on CR disruption/sleep and metabolic endpoints. Collectively, results from this project will help shed important new light on air pollution, its impact on CR and cardiometabolic disorders and provide influential data on protective effects of personal intervention strategies, that together could change public health policy.