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

• 批准号: 7777140
• 负责人: NAOMI K FUKAGAWA
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-11 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777140
• 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 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; Heart Diseases; Hematopoietic; 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; 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; in vivo; lung injury; macrophage; mortality; particle; planetary Atmosphere; public health relevance; response

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，已报告了意外低浓度的颗粒空气污染对健康的不良影响，导致科学家和公共卫生官员得出结论，长期暴露于燃烧相关的细颗粒空气污染是心脏和肺部疾病的重要环境风险因素。尽管许多研究检查了石油柴油（petrodiesel）废气排放对呼吸系统的影响，但导致报告的不利人类健康影响的机制以及颗粒的哪些特征引发不利过程仍然难以捉摸。在美国和欧洲，由植物油或动物脂肪制成的生物柴油作为未来的能源正在获得动力。生物柴油通常与传统柴油混合，排放测试表明，生物柴油排放物中含有较低水平的碳氢化合物，一氧化碳和颗粒物（PM），但可溶性有机部分浓度较高。待检验的假设是，与石油柴油相比，生物柴油燃烧产生的颗粒物对肺部的不良影响较小。生物学效应将包括细胞死亡和代偿性细胞生长以及炎症反应，通过体外人肺上皮细胞和巨噬细胞中的促分裂原活化蛋白激酶（MAPK）和核因子-κ B（NF-（B）信号传导通路的激活以及体内鼠吸入肺损伤模型进行调节。Cot（cancer osaka thyroid and rat homologue，肿瘤进展基因座2或Tp 12），一种人类原癌基因，是MAP激酶（MAPK 3 K）家族中的丝氨酸/苏氨酸激酶，其在造血和肺组织中表达。COT/Tp 1/2已显示诱导ERK 1/2和NF-β B并在T细胞活化中起作用。我们计划测试来自石油和生物柴油燃烧的颗粒是否会差异性地激活COT/Tp 1/2并随后差异性地激活ERK 1/2和NF-β B途径，从而导致特征性细胞因子/趋化因子应答和细胞凋亡与增殖之间平衡的转变。本提案中获得的数据将为未来的研究奠定基础，这些研究旨在确定导致肺损伤的废气排放的特定成分以及可能减弱致病反应的潜在干预措施。 公共卫生相关性：生物柴油被吹捧为能源独立的重要战略，以及农业生产和减少运输部门对环境影响的可持续性，但与石油柴油一样，生物柴油的燃烧会产生颗粒空气污染。据报道，空气污染中的颗粒物浓度出乎意料地低，对健康产生不利影响，导致科学家和公共卫生官员得出结论，长期暴露于与燃烧有关的颗粒空气污染是心脏和肺部疾病的重要环境风险因素。尽管人们相信生物燃料可能对环境和人类健康更好，关于生物柴油排放物的生物和健康影响的信息非常有限，因此本项目将比较和对比石油燃烧产生的排放颗粒的生物影响，和生物柴油，努力为未来的研究奠定基础，旨在阐明负责之间的重要关系的机制，空气中的颗粒物和肺病及心脏病，以及制定减少空气污染对健康的不利影响的方法。