Tlp2/COT Regulation of ERK1/2 and NF-kB in Response to Particulates

Tlp2/COT 对 ERK1/2 和 NF-kB 响应颗粒物的调节

基本信息

批准号：
8013037
负责人：
NAOMI K FUKAGAWA
金额：
$ 7.45万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
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：
2010-01-11 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013037
关键词：
Agriculture Air Pollution Animals Apoptosis Area Aromatic Compounds Attenuated Belief Biological Breathing Caliber Carbon Monoxide Cardiopulmonary Cardiovascular Diseases Cardiovascular system Cell Death Cells Characteristics Chemistry Data Development Diesel Exhaust Diesel Fuels Disease Distal Endotoxins Energy-Generating Resources Engineering Environment Environmental Impact Environmental Risk Factor Epidemiology Epithelial Cells Equilibrium Europe Exposure to Family Fatty acid glycerol esters Fibrosis Future Health Heart Diseases Homologous Gene Human Human Cell Line Hydrocarbons In Vitro Inflammation Mediators Inflammatory Response Intervention Lead Letters Link Lung Lung diseases MAP Kinase Kinase Kinase MAP3K8 gene MAPK3 gene Malignant Neoplasms Malignant neoplasm of lung Mitogen-Activated Protein Kinases Modeling Morbidity - disease rate Mus NF-kappa B Nose Particle Size Particulate Particulate Matter Pathogenesis Pathway interactions Petroleum Play Pneumonia Process Production Property Protein-Serine-Threonine Kinases Proto-Oncogenes Public Health Pulmonary Heart Disease Rattus Regulation Reporting Research Respiratory System Role Schools Scientist Signal Pathway Source Structure of parenchyma of lung Sulfur T-Cell Activation Testing Thyroid Gland Transportation Ultrafine Universities Vegetable Oils Vermont base cell growth chemokine cytokine design exhaust hematopoietic tissue in vivo lung injury macrophage mortality particle planetary Atmosphere public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Since the 1970's, adverse health effects have been reported at unexpectedly low concentrations of particulate air pollution, leading scientists and public health officials to conclude that long-term exposure to combustion-related fine particulate air pollution is a significant environmental risk factor for heart and lung diseases. Despite numerous studies examining the effects of petroleum diesel (petrodiesel) exhaust emissions on the respiratory system, the mechanisms responsible for the reported adverse human health effects and which features of the particles initiate adverse processes remain elusive. Biodiesel fuel made from vegetable oil or animal fat is gaining momentum as the energy source of the future both in the U.S. and Europe. Biodiesel is typically blended into conventional diesel fuel, and emission testing has shown that biodiesel emissions contain reduced levels of hydrocarbons, carbon monoxide and particulate matter (PM) but a higher concentration of soluble organic fraction. The hypothesis to be tested is that particulates from biodiesel combustion will have less adverse lung effects compared to those from petrodiesel. The biological effects will include cell death and compensatory cell growth and inflammatory responses, regulated by the activation of the Mitogen-activated Protein Kinase (MAPK) and Nuclear Factor-kappa B (NF-(B) signaling pathways in human lung epithelial cells and macrophages in vitro and an in vivo murine inhalation model of lung injury. Cot (cancer osaka thyroid and rat homologue, tumor progression locus 2 or Tpl2), a human proto-oncogene, is a serine/threonine kinase in the MAP Kinase kinase kinase (MAPK3K) family that is expressed in hematopoietic and lung tissues. COT/Tpl2 has been shown to induce ERK1/2 and NF-(B and play a role in T cell activation. We plan to test whether particulates from petro- and biodiesel combustion will differentially activate COT/Tpl2 and subsequently differentially activate ERK1/2 and NF-(B pathways leading to characteristic cytokine/chemokine responses and a shift in the balance between cell apoptosis and proliferation. The data to be obtained in this proposal will lay the groundwork for future studies aimed at identifying the specific components of exhaust emissions that lead to lung injury and the potential interventions that may attenuate the pathogenic responses. PUBLIC HEALTH RELEVANCE: Biodiesel has been touted as an important strategy for energy independence as well as sustainability in terms of agricultural production and reduced environmental impact from the transportation sector, but as with petrodiesel, combustion of biodiesel produces particulate air pollution. Adverse health effects have been reported at unexpectedly low concentrations of particulate matter in air pollution, leading scientists and public health officials to conclude that long-term exposure to combustion-related particulate air pollution is a significant environmental risk factor for heart and lung diseases. Despite the belief that biofuels may be better for the environment and for human health, there is very limited information about the biological and health effects of biodiesel emissions so this project will compare and contrast the biological effects of emission particles from the combustion of petro- and biodiesel in an effort to lay the groundwork for future studies aimed at elucidating the mechanisms responsible for the significant relationship between airborne particulates and lung and heart disease and at developing approaches to reduce the adverse health consequences of air pollution.

描述（由申请人提供）：自 20 世纪 70 年代以来，据报道，颗粒物空气污染浓度出乎意料地低，对健康产生不利影响，科学家和公共卫生官员得出这样的结论：长期暴露于与燃烧相关的细颗粒物空气污染对健康产生了重大影响。心脏病和肺病的环境危险因素。尽管有大量研究考察了石油柴油（石化柴油）废气排放对呼吸系统的影响，但造成所报告的人类健康不良影响的机制以及颗粒的哪些特征引发不良过程仍然难以捉摸。在美国和欧洲，由植物油或动物脂肪制成的生物柴油燃料作为未来能源的势头正在增强。生物柴油通常混合到传统柴油中，排放测试表明，生物柴油排放物中碳氢化合物、一氧化碳和颗粒物 (PM) 的含量降低，但可溶性有机成分的浓度较高。要测试的假设是，与石化柴油燃烧产生的颗粒相比，生物柴油燃烧产生的颗粒对肺部的不利影响较小。生物效应包括细胞死亡、代偿性细胞生长和炎症反应，由人肺上皮细胞和巨噬细胞中丝裂原激活蛋白激酶 (MAPK) 和核因子-κ B (NF-(B) 信号通路的激活调节肺损伤的体外和体内小鼠吸入模型 Cot（大阪甲状腺癌和大鼠同源物，肿瘤进展基因座 2 或 Tpl2），一种人类原癌基因， COT/Tpl2 是 MAP 激酶激酶激酶 (MAPK3K) 家族中的一种丝氨酸/苏氨酸激酶，在造血组织和肺组织中表达，已被证明可诱导 ERK1/2 和 NF-(B)，并在 T 细胞激活中发挥作用。我们计划测试石油和生物柴油燃烧产生的颗粒物是否会差异激活 COT/Tpl2，并随后差异激活 ERK1/2 和 NF-(B 途径，从而导致特征细胞因子/趋化因子反应以及细胞凋亡和增殖之间平衡的转变将为未来的研究奠定基础，旨在确定导致肺损伤的废气排放的特定成分以及潜在的干预措施。可能会减弱致病反应。公共健康相关性：生物柴油被认为是能源独立、农业生产可持续性和减少运输部门对环境影响的重要战略，但与石化柴油一样，生物柴油的燃烧会产生颗粒空气污染。据报道，空气污染中颗粒物浓度出乎意料地低，对健康产生不利影响，科学家和公共卫生官员得出结论，长期暴露于与燃烧相关的颗粒物空气污染是导致心脏和肺部疾病的一个重要环境风险因素。尽管人们相信生物燃料可能对环境和人类健康更好，但有关生物柴油排放的生物和健康影响的信息非常有限，因此该项目将比较和对比石油和天然气燃烧排放颗粒的生物影响。生物柴油，旨在为未来的研究奠定基础，旨在阐明空气中颗粒物与肺病和心脏病之间的重要关系的机制，并开发减少空气污染对健康造成的不利影响的方法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex-specific metabolic adaptations from in utero exposure to particulate matter derived from combustion of petrodiesel and biodiesel fuels.

由于在子宫内暴露于石化柴油和生物柴油燃料燃烧产生的颗粒物而产生的性别特异性代谢适应。

DOI：
10.1016/j.chemosphere.2023.140480
发表时间：
2023-10-01
期刊：
Chemosphere
影响因子：
8.8
作者：
T. Jetton;Oban T. Galbraith;Mina Peshavaria;Elizabeth A. Bonney;B. Holmén;Naomi K. Fukagawa
通讯作者：
Naomi K. Fukagawa

Soy biodiesel and petrodiesel emissions differ in size, chemical composition and stimulation of inflammatory responses in cells and animals.

大豆生物柴油和石化柴油的排放量在大小、化学成分以及对细胞和动物炎症反应的刺激方面有所不同。

DOI：
10.1021/es403146c
发表时间：
2013
期刊：
Environmental science & technology
影响因子：
11.4
作者：
Fukagawa, Naomi K.;Li, Muyao;Poynter, Matthew E.;Palmer, Brian C.;Parker, Erin;Kasumba, John;Holmen, Britt A.
通讯作者：
Holmen, Britt A.