Airborne Particulate Matter, Endoplasmic Reticulum Stress and Hepatic Lipid Dysre

描述(申请人提供)：空气污染是一个持续存在的公众健康问题，对于一般人来说，特别是对那些生活在交通密集或工业活动地区的人来说。流行病学研究和临床观察证实，吸入空气颗粒物(PM)与代谢性疾病的易感性之间存在联系。然而，对空气污染相关发病机制的分子和细胞基础的准确理解仍然难以捉摸。最近，我们积累了具有挑衅性的初步信息，即暴露于环境相关的细范围空气PM(直径2.5？m，PM2.5)可诱导内质网(ER)应激，并随后激活小鼠肝脏的未折叠蛋白反应(UPR)。环境PM2.5激活UPR信号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包括过氧化体增殖物激活受体在内的关键肝脂调节因子表达的改变有关。(PPAR？)和对氧磷酶-1(PON-1)，异常的肝脏脂滴堆积，以及肥胖动物糖/胰岛素稳态受损。这些观察结果导致了一种新的假设，即内质网应激反应可能是环境PM2.5引发其毒性效应的关键，后者导致肝脏脂肪调节失调和随后的代谢紊乱。在这项应用中，我们将使用一个“真实世界”的PM暴露系统，用动物模型概括个人长期暴露在与环境相关的PM2.5中。通过这种暴露系统、分子和细胞方法以及药理学手段，我们将研究环境PM2.5诱导内质网应激和UPR激活导致肝脂代谢失调的机制。具体地说，在目标1中，我们将使C57BL/6J小鼠沿着或与高脂饮食一起暴露于浓缩的PM2.5，然后表征内质网应激以及肝脏和其他组织中的UPR信号通路。在目标2中，我们将探讨PM2.5诱导的内质网应激反应在促进肝脂代谢紊乱中的分子基础。我们还将评估PM2.5诱导的压力是否代表着在肥胖动物中触发非酒精性脂肪性肝病(NAFLD)的“打击”。预计拟议的研究将揭示PM2.5暴露和ER压力之间前所未有的联系。这些发现不仅将有助于更好地了解空气中PM致病的分子和细胞机制，而且将对与空气污染相关的代谢性疾病的预防和治疗的医疗保健产生重大影响。 与公共健康相关：空气污染是城市地区普通民众的一个持续的公共健康问题，特别是对那些生活在交通密集或工业活动地区的人。大气颗粒物(PM)通过激活内质网(ER)应激反应，对肝脏脂代谢紊乱产生毒性作用。拟议的研究不仅对于更好地了解空气颗粒物驱动疾病发病的分子和细胞基础至关重要，而且还将为预防和治疗与空气污染相关的系统性疾病提供有价值的信息。

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.