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

（昼夜节律）昼夜节律紊乱是空气污染中心脏代谢风险的调节因素

• 批准号: 10452498
• 负责人: Sanjay Rajagopalan
• 金额: $ 96.04万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-17 至 2029-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452498
• 关键词: Acquired Immunodeficiency Syndrome; Air Pollution; Animals; Biological; Cardiometabolic Disease; Cardiovascular system; Circadian Dysregulation; Circadian Rhythms; Data; Disease; Environmental Risk Factor; Epigenetic Process; Famines; Foundations; Goals; Health; Health Policy; Heart; Human; Influentials; Insulin Resistance; Intervention; Intervention Trial; Investigation; Light; Link; Malaria; Mediating; Mediator of activation protein; Mendelian randomization; Metabolic; Metabolic dysfunction; Morbidity - disease rate; National Institute of Environmental Health Sciences; Non-Insulin-Dependent Diabetes Mellitus; Particulate Matter; Pathway interactions; Pollution; Public Health; Research; Risk; Sleep disturbances; Translational Research; Tuberculosis; Vulnerable Populations; War; cardiometabolic risk; cardiovascular risk factor; cohort; genome wide association study; innovation; mortality; personalized intervention; personalized strategies; prevent; programs; protective effect; success; translational clinical trial; translational framework

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.

抽象的 <2.5μm 的颗粒物空气污染 (PM2.5) 是全球主要的环境风险因素，贡献更多 全球死亡率比艾滋病、疟疾、结核病和战争/饥荒的总和还要多。相关的健康风险 PM2.5 主要由心血管 (CV) 原因引起，数据支持对公共健康产生重大影响 由于 2 型糖尿病等疾病。以我们研究计划取得的巨大成功为基础， 很大一部分为我们理解PM2.5诱发的机制提供了基础依据 针对心脏代谢疾病，我们提出了一个创新的转化研究框架。我们的新数据 通过表观遗传学提供 PM2.5 暴露与昼夜节律 (CR) 破坏之间令人信服的联系 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，我们提出了一项雄心勃勃的计划，其中包括 8 年内的 3 个目标， 涵盖涉及集中环境 PM2.5 暴露（动物）和人类的协调研究 整个环境暴露范围的干预试验，由基因组结果预测和支持 广泛关联和孟德尔随机化方法，将确定空气污染介导的途径 简历风险。利用正在进行的利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，并通过一项涉及减轻空气污染的新研究（ITS-MY-AIR）， 我们将评估减少暴露对 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为空气污染及其对 CR 和心脏代谢的影响提供重要的新线索 疾病并提供有关个人干预策略的保护作用的有影响力的数据，这些数据共同可以 改变公共卫生政策。