PM Induced Altered Regulation of G1 Cyclins in AEC

PM 诱导 AEC 中 G1 细胞周期蛋白调节的改变

• 批准号: 7478542
• 负责人: DAYA UPADHYAY
• 金额: $ 13.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478542
• 关键词: Acute; Air Pollution; Airborne Particulate Matter; Alveolar; Apoptosis; Biological; CDK2 gene; CDK4 gene; CDK5 gene; Cardiopulmonary; Cell Cycle; Cell Cycle Arrest; Cell Cycle Deregulation; Cell Cycle Progression; Cell Cycle Regulation; Cessation of life; Chronic; Cyclin D1; Cyclin-Dependent Kinases; Cyclins; DNA; DNA Damage; DNA Repair; Data; Epithelial Cells; Feedback; Free Radicals; Functional disorder; G1 Phase; Gene Targeting; Generations; Injury; Investigation; Iron; Link; Lipids; Lung; Lung diseases; Malignant neoplasm of lung; Mediating; Mitochondria; Molecular; Morbidity - disease rate; Oxidants; Oxidative Stress; Particulate; Pathway interactions; Phase; Post-Translational Protein Processing; Proteins; Reactive Oxygen Species; Regulation; Research Personnel; Second Messenger Systems; Signal Transduction; Testing; Toxic effect; Work; base; cell injury; cyclin G1; injury and repair; mortality; particle; programs; repaired; research study; response; second messenger

DESCRIPTION (provided by applicant): Ambient air pollution particle (PM) is associated with increased morbidity and mortality resulting from acute and chronic cardiopulmonary injury including lung cancer. Recent investigations have demonstrated that PM is genotoxic to alveolar epithelial cell (AEC) by causing DMA damage and apoptosis. The extent of AEC injury and repair are critical determinants of the toxic potential of PM. The precise cellular and molecular mechanisms underlying the toxic pulmonary effects of PM are not fully established. However, the mechanisms may depend upon the ability of PM to interact with and modify a spectrum of biomolecules including DNA, lipids, and proteins. Accumulating evidence implicate PM induced DNA damage and apoptosis due to iron-derived reactive oxygen species (ROS) as important second messengers of toxicity due to a variety of particulates. It is known that various DNA-damaging agents such as oxidants generate signals that converge to either cell cycle arrest or apoptosis. Control of cell cycle progression in response to oxidative stress is linked to activation of a checkpoint mechanism operating before entry into the S phase of the cell cycle. A feedback control is activated that acts as a brake on the cell cycle to inhibit entry into the S phase until DNA repair is completed. Progression through the G1 phase and the G1-S transition involves sequential assembly and activation of key regulators of the cell cycle machinery, the Cyclins and cyclin-dependent kinases (CDKs). However, there is no information on airborne particulate matter induced regulation of this cell cycle machinery. Our preliminary data show that PM induces cell cycle arrest and alters regulation of G1 Cyclins and cyclin-dependent kinase in AEC. The specific aims of this proposal are 1) To determine whether ambient air pollution particulates induce cell cycle arrest via altered regulation of G1 cyclins by generation of reactive oxygen species in AEC. 2) To determine whether iron derived free radicals mediate PM-induced altered expression and posttranslational modification of cell cycle regulatory target genes in AEC. 3) To determine whether PM-induced cell cycle arrest is mediated by altered regulation of G1 Cyclins and CDKs that activate mitochondria) death pathway. Our proposed work will enable us to understand the molecular and biological basis of pathophysiology of ambient airborne particulate induced lung diseases.

描述（由申请人提供）： 环境空气污染颗粒物（PM）与急性和慢性心肺损伤（包括肺癌）的发病率和死亡率增加有关。最近的研究表明，PM对肺泡上皮细胞（AEC）具有遗传毒性，可引起DNA损伤和细胞凋亡。AEC损伤和修复的程度是PM潜在毒性的关键决定因素。PM的毒性肺效应的确切细胞和分子机制尚未完全建立。然而，这些机制可能取决于PM与包括DNA、脂质和蛋白质在内的生物分子的光谱相互作用并对其进行修饰的能力。越来越多的证据表明，铁源性活性氧（ROS）作为多种颗粒物毒性的重要第二信使，可导致PM诱导的DNA损伤和细胞凋亡。 已知各种DNA损伤剂如氧化剂产生会聚于细胞周期停滞或凋亡的信号。响应于氧化应激的细胞周期进程的控制与进入细胞周期的S期之前操作的检查点机制的激活有关。一个反馈控制被激活，作为细胞周期的刹车，以抑制进入S期，直到DNA修复完成。通过G1期和G1-S转变的进展涉及细胞周期机制的关键调节因子，细胞周期蛋白和细胞周期蛋白依赖性激酶（CDK）的顺序组装和激活。然而，没有关于空气中颗粒物诱导的细胞周期调节机制的信息。 我们的初步数据表明，PM诱导AEC细胞周期阻滞，并改变G1期细胞周期蛋白和细胞周期蛋白依赖性激酶的调节。本提案的具体目的是：1）确定环境空气污染颗粒物是否通过在AEC中产生活性氧来改变G1细胞周期蛋白的调节而诱导细胞周期停滞。2)确定铁源性自由基是否介导PM诱导的AEC细胞周期调控靶基因的表达改变和翻译后修饰。3)确定PM诱导的细胞周期阻滞是否通过G1期细胞周期蛋白和激活线粒体死亡途径的CDK的调节改变介导。我们提出的工作将使我们能够了解周围空气颗粒物引起的肺部疾病的病理生理学的分子和生物学基础。