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

基本信息

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
项目类别：
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

项目摘要

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）：空气污染是公众健康的一个持续问题，特别是对于居住在交通或工业活动密集地区的人们来说。流行病学研究和临床观察已证实吸入空气颗粒物（PM）与代谢性疾病易感性之间存在联系。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，我们积累了令人兴奋的初步信息，即暴露于与环境相关的细范围空气 PM（直径 < 2.5 µm，PM2.5）会诱导内质网 (ER) 应激，并随后激活小鼠肝脏中的未折叠蛋白反应 (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 ER 应激反应与关键肝脂质调节因子（包括过氧化物酶体增殖物激活受体）表达的改变相关。 (PPAR?) 和对氧磷酶 1 (PON-1)、异常的肝脏脂滴积累以及肥胖动物的葡萄糖/胰岛素稳态受损。这些观察结果得出了一个新的假设，即内质网应激反应可能对于环境 PM2.5 引发其毒性作用至关重要，从而导致肝脂质失调和随后的代谢紊乱。在此应用中，我们将使用“真实世界”PM 暴露系统，通过动物模型重现个人长期暴露于环境相关 PM2.5 的情况。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。具体来说，在目标 1 中，我们将让 C57BL/6J 小鼠接触浓缩 PM2.5 并同时或结合高脂肪饮食，然后表征肝脏和其他组织中的 ER 应激和 UPR 信号通路。在目标 2 中，我们将研究 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 引起的压力是否代表了引发肥胖动物非酒精性脂肪肝 (NAFLD) 的“打击”。拟议的研究预计将揭示 PM2.5 暴露与 ER 应激之间前所未有的联系。这些发现不仅有助于更好地了解空气中PM引起的发病机制的分子和细胞机制，而且还将对与空气污染相关的代谢性疾病的预防和治疗产生重大影响。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，特别是对于居住在交通或工业活动密集地区的人们来说。空气颗粒物（PM）通过激活内质网（ER）应激反应，对肝脏脂质代谢失调产生毒性作用。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机制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全身性疾病提供有价值的信息。