Airborne Particulate Matter, Endoplasmic Reticulum Stress and Hepatic Lipid Dysre

描述（由申请人提供）：空气污染是一个持续的公众健康问题，特别是对于那些生活在交通密集或工业活动地区的人。流行病学研究和临床观察证实了吸入空气颗粒物（PM）与代谢性疾病易感性之间的联系。然而，对驱动空气污染相关发病机制的分子和细胞基础的精确理解仍然难以捉摸。最近，我们积累了一些具有挑衅性的初步信息，暴露于与环境有关的空气中pm2.5的细范围(直径< 2.5 ？m, PM2.5)诱导小鼠肝脏内质网（ER）应激并随后激活未折叠蛋白反应（UPR）。环境PM2.5对UPR信号的激活依赖于活性氧和钙信号。此外，pm2.5诱导的内质网应激反应与关键肝脂质调节因子的表达改变有关，包括过氧化物酶体增殖物激活受体？（PPAR?）和对氧磷酶1 (PON-1)，异常的肝脂滴积累，以及受损的葡萄糖/胰岛素稳态。这些观察结果导致了一个新的假设，即内质网应激反应可能对环境PM2.5的毒性作用至关重要，从而导致肝脂质失调和随后的代谢紊乱。在这个应用中，我们将使用一个“真实世界”的PM暴露系统，用动物模型来概括个人慢性暴露于环境相关的PM2.5。通过这种暴露系统、分子和细胞方法以及药理学工具，我们将研究环境PM2.5诱导内质网应激和UPR激活导致肝脏脂质代谢失调的机制。具体来说，在Aim 1中，我们将C57BL/6J小鼠暴露在高浓度PM2.5中，同时或与高脂肪饮食结合，然后表征内质网应激和肝脏和其他组织中的UPR信号通路。在Aim 2中，我们将研究pm2.5诱导内质网应激反应在促进肝脏脂质代谢失调中的分子基础。我们还将评估pm2.5诱导的应激是否会引发肥胖动物的非酒精性脂肪性肝病（NAFLD）。预计拟议的研究将揭示PM2.5暴露与内质网压力之间前所未有的联系。这些发现不仅有助于更好地理解空气中PM诱导的发病机制的分子和细胞机制，而且对预防和治疗与空气污染相关的代谢性疾病的医疗保健具有重要影响。

DESCRIPTION (provided by applicant): Air pollution is a sustained problem of public health for the general population, especially for those that live in areas of intensive traffic or industrial activity. Epidemiological study and clinical observation have confirmed a link between inhaled air particulate matter (PM) and susceptibility to metabolic diseases. However, a precise understanding of molecular and cellular basis that drives air pollution-associated pathogenesis remains elusive. Recently we have accumulated provocative preliminary information that exposure to environmentally relevant air PM in fine ranges (diameter < 2.5 ?m, PM2.5) induces endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR) in the mouse liver. Activation of the UPR signaling by ambient PM2.5 relies on reactive oxygen species and calcium signals. Furthermore, PM2.5-induced ER stress response is correlated with altered expression of key hepatic lipid regulators including peroxisome proliferator-activated receptor ? (PPAR?) and paraoxonase 1 (PON-1), abnormal hepatic lipid droplet accumulation, as well as impaired glucose/insulin homeostasis in obese animals. These observations lead to a novel hypothesis that ER stress response may be crucial for ambient PM2.5 to elicit its toxic effect that causes hepatic lipid dysregulation and subsequent metabolic disorders. In this application, we will use a "real world" PM exposure system to recapitulate personal, chronic exposure to environmental relevant PM2.5 with animal models. Through this exposure system, molecular and cellular approaches, as well as pharmacologic tools, we will investigate the mechanisms by which ambient PM2.5 induces ER stress and the UPR activation that leads to dysregulation of hepatic lipid metabolism. Specifically, in Aim 1, we will expose C57BL/6J mice to concentrated PM2.5 along or in combination with a high-fat diet and then characterize ER stress and the UPR signaling pathways in the liver and other tissues. In Aim 2, we will investigate the molecular basis for PM2.5-induced ER stress response in promoting dysregulation of hepatic lipid metabolism. We will also evaluate whether PM2.5-induced stress represents a "hit" that triggers non-alcoholic fatty liver disease (NAFLD) in obese animals. The proposed studies are anticipated to reveal an unprecedented link between PM2.5 exposure and ER stress. The findings will not only contribute to a better understanding of the molecular and cellular mechanisms underlying airborne PM- induced pathogenesis, but will also have high impact on the medical care from the prevention to treatment of metabolic diseases associated with air pollution. PUBLIC HEALTH RELEVANCE: Air pollution is a sustained problem of public health for the general population in urban areas, especially for those that live in areas of intensive traffic or industrial activity. Air particulate matter (PM) elicits its toxic effects on dysregulation of liver lipid metabolism through activating endoplasmic reticulum (ER) stress response. The proposed studies will not only be critical for a better understanding of the molecular and cellular basis by which air PM drives disease pathogenesis, but will also provide valuable information for the prevention and treatment of air pollution-associated systemic diseases.