Airborne Particulate Matter, Endoplasmic Reticulum Stress and Hepatic Lipid Dysre

空气颗粒物、内质网应激和肝脂质异常

• 批准号: 7991190
• 负责人: Kezhong Zhang
• 金额: $ 20.32万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991190
• 关键词: Air; Air Pollution; Airborne Particulate Matter; Animal Model; Animals; Applications Grants; Area; Breathing; Calcium Signaling; Caliber; Caring; Cellular Stress; Chronic; Clinical; Diet; Disease; Endoplasmic Reticulum; Epidemiologic Studies; Exposure to; Fatty acid glycerol esters; Gene Expression; General Population; Glucose; Hepatic; Homeostasis; Insulin; Knowledge; Lead; Life; Link; Lipids; Liver; Liver diseases; Medical; Metabolic; Metabolic Diseases; Molecular; Morbidity - disease rate; Mus; Obesity; Paraoxonase 1; Particulate Matter; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Predisposition; Prevention; Proteins; Public Health; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Steatohepatitis; Stress; System; Systemic disease; Testing; Tissues; Toxic effect; base; biological adaptation to stress; endoplasmic reticulum stress; lipid metabolism; macrophage; mortality; non-alcoholic fatty liver; novel; protein misfolding; public health relevance; response; tool; trafficking; urban area

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.

描述（由申请人提供）：空气污染是一个持续的公共卫生问题，对一般人群，特别是那些生活在交通密集或工业活动的地区。流行病学研究和临床观察已经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，我们已经积累了挑衅性的初步信息，暴露于环境相关的空气PM在罚款范围（直径< 2.5？m，PM2.5）诱导内质网（ER）应激和随后激活的未折叠蛋白反应（UPR）在小鼠肝脏。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改变表达的关键肝脏脂质调节，包括过氧化物酶体增殖物激活受体？(PPAR?)和对氧磷酶1（PON-1）、异常肝脂滴积聚以及肥胖动物中受损的葡萄糖/胰岛素稳态。这些观察结果导致了一个新的假设，ER应激反应可能是至关重要的环境PM2.5引起其毒性作用，导致肝脏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“真实的世界”PM暴露系统，以动物模型来概括个人长期暴露于环境相关的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ER应激和UPR激活导致肝脏脂质代谢失调的机制。具体而言，在目标1中，我们将C57 BL/6 J小鼠暴露于浓缩的PM2.5沿着或与高脂肪饮食组合，然后表征ER应激和肝脏和其他组织中的UPR信号通路。目的2：研究PM2.5诱导的内质网应激反应促进肝脏脂质代谢失调的分子基础。我们还将评估PM2.5诱导的压力是否代表引发肥胖动物非酒精性脂肪肝（NAFLD）的“打击”。预计拟议的研究将揭示PM2.5暴露与ER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PM诱导发病机制的分子和细胞机制，而且还将对预防和治疗与空气污染相关的代谢性疾病的医疗保健产生重大影响。 公共卫生相关性：空气污染是城市地区普通民众的一个持续的公共卫生问题，特别是对那些生活在交通密集或工业活动地区的人来说。大气颗粒物（PM）通过激活内质网（ER）应激反应，发挥其对肝脏脂质代谢紊乱的毒性作用。拟议的研究不仅对更好地了解空气PM驱动疾病发病机制的分子和细胞基础至关重要，而且还将为预防和治疗空气污染相关的全身性疾病提供有价值的信息。