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

摘要 <2.5µm的颗粒物空气污染（PM2.5）是全球主要的环境风险因素， 比艾滋病、疟疾、肺结核和战争/饥荒的总和还要多。相关的健康风险 PM2.5主要来自心血管（CV）原因，数据支持重大公共卫生影响 这是由于2型糖尿病等疾病。在我们研究计划取得实质性成功的基础上， 为我们理解PM2.5引起的大气污染的机理提供了基础性的依据 心脏代谢疾病，我们提出了一个创新的框架，翻译的调查。我们的新数据 通过表观遗传学提供PM2.5暴露和昼夜节律（CR）破坏之间的令人信服的联系 重编程，导致代谢功能障碍和胰岛素抵抗。根据NIEHS 转化研究框架，我们提出了一个雄心勃勃的计划，包括3个目标，在8年内， 包括涉及集中环境PM2.5暴露（动物）和人类的协调研究 在整个环境暴露范围内进行干预试验，并得到基因组结果的预测和支持 广泛的关联和孟德尔随机化方法，将确定空气污染介导的途径 CV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临床试验， 北京的弱势群体，并通过一项涉及缓解空气污染的新研究（ITS-MY-AIR）， 我们将评估暴露减少对CR中断/睡眠和代谢终点的影响。总的来说， 该项目的结果将有助于揭示空气污染及其对CR和心脏代谢的影响 疾病，并提供有影响力的数据，个人干预策略的保护作用，这两者结合起来， 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.