Oxidant signaling for airway remodeling and inflammation

气道重塑和炎症的氧化信号

• 批准号: 8311704
• 负责人: YUICHIRO Justin SUZUKI
• 金额: $ 34.19万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311704
• 关键词: Affect; Airway Resistance; Allergens; Annexin A1; Annexins; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Asthma; Cell Count; Cell Proliferation; Cell Survival; Cellular biology; Chronic Disease; Core-Binding Factor; Cysteine; Data; Development; Endothelin-1; Event; Genetic Transcription; Goals; Human; Hydrogen Peroxide; Hydroxyl Radical; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Iron; Iron Chelation; Knowledge; Laboratories; Lead; Lung; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metals; Molecular; Morbidity - disease rate; Mus; New Agents; Obstruction; Oxidants; Patients; Platelet-Derived Growth Factor; Play; Production; Proteins; Reaction; Reactive Oxygen Species; Reagent; Regulation; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transcription factor genes; Ubiquitination; United States; Up-Regulation; Work; abstracting; airway inflammation; airway remodeling; base; cell growth; cell growth regulation; computerized data processing; design; expectation; free radical oxygen; in vivo; innovation; mRNA Expression; mortality; multicatalytic endopeptidase complex; novel; novel therapeutics; overexpression; oxidation; prevent; protein expression; respiratory smooth muscle

DESCRIPTION (provided by applicant): Asthma is a chronic disorder of the airways that is characterized by airflow obstruction, inflammation, hyperreactivity and remodeling. Airway remodeling is, in part, due to increased smooth muscle cell growth, and immunomodulatory roles of airway smooth muscle cells have recently been recognized. Reactive oxygen species have been shown to serve as signaling mediators in airway smooth muscle cells. Mechanisms of how reactive oxygen species are involved in cell signaling events, however, remain largely undefined. Lack of such knowledge interferes with the development of new therapeutic strategies that are designed to prevent and/or treat asthma. My long-range goal is to understand the mechanism of reactive oxygen species signaling in airway smooth muscle cells. The objective of this application is to evaluate the mechanism and functions of annexin A1 (lipocortin) carbonylation induced by mediators of asthma. The central hypothesis is that reactive oxygen species produced by mediators of asthma including platelet-derived growth factor (PDGF) and endothelin-1 promote carbonylation of annexin A1 (which regulates inflammation and cell growth) as a signal transduction mechanism. The hypothesis has been formulated on the basis of strong preliminary data in smooth muscle cells which suggest that: (i) PDGF and endothelin-1, important mediators of asthma, promote protein carbonylation; (ii) Mass spectrometry identified that annexin A1 (an anti-inflammatory, anti-proliferative and pro-apoptotic molecule), is one protein that is carbonylated; (iii) Annexin A1 interacts with proteins which promote proliferation and survival of smooth muscle cells and inflammatory responses; (iv) Overexpression of annexin A1 reduces smooth muscle cell number, (v) Carbonylation of annexin A1 is followed by proteasome- dependent degradation, and (vi) Iron chelation inhibits PDGF-induced upregulation of bcl-2 and interleukin-13 mRNA expression in human airway smooth muscle cells. Further, in vivo treatment of mice with allergens to induce asthma promoted degradation of annexin A1. The rationale for the proposed research is that, once knowledge of signaling pathways that regulate cell growth and inflammatory responses in airway smooth muscle cells has been obtained, it will lead to new strategies that can be used to prevent and/or treat asthma. The objective of the application will be accomplished by pursuing three specific aims: 1) Identify the mechanism of annexin A1 carbonylation by cell signaling mediators in human airway smooth muscle cells, 2) Determine the role of protein carbonylation in the mechanism of annexin A1 degradation, and 3) Define the roles of annexin A1 in the regulation of airway smooth muscle cell growth and inflammatory responses. The proposed work is innovative because it will investigate a novel mechanism for reactive oxygen species signaling and study the novel roles of annexin A1 in airway smooth muscle regulation for cell growth and inflammatory responses. It is my expectation that mediators of asthma including PDGF and endothelin-1 promote metal-catalyzed annexin A1 carbonylation that specifically influences cell growth, apoptotic and inflammatory signaling via mechanisms involving proteasomes. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions for asthma. In addition, the results will fundamentally advance the field of lung cell biology. (End of Abstract)

描述(由申请人提供)： 哮喘是一种慢性呼吸道疾病，以气流阻塞、炎症、高反应性和重塑为特征。气道重塑在一定程度上是由于增加了平滑肌细胞的生长，最近人们认识到了气道平滑肌细胞的免疫调节作用。已有研究表明，活性氧在气道平滑肌细胞中起信号调节作用。然而，关于活性氧物种如何参与细胞信号事件的机制在很大程度上仍不清楚。缺乏这类知识干扰了旨在预防和/或治疗哮喘的新治疗策略的发展。我的长期目标是了解呼吸道平滑肌细胞中活性氧的信号转导机制。本应用的目的是评价哮喘介质诱导的膜联蛋白A1(Lipocortin)甲基化的机制和功能。中心假说是哮喘介质产生的活性氧物种，包括血小板衍生生长因子(PDGF)和内皮素-1，促进膜联蛋白A1(调节炎症和细胞生长)的羰化，作为一种信号转导机制。这一假说是建立在强大的平滑肌细胞初步数据的基础上的，这些数据表明：(I)PDGF和ET-1是哮喘的重要介质，促进蛋白质的羰化；(Ii)质谱仪鉴定Annexin A1(一种抗炎、抗增殖和促凋亡的分子)是一种羰化的蛋白质；(Iii)Annexin A1与促进平滑肌细胞增殖、存活和炎症反应的蛋白质相互作用；(4)膜联蛋白A1的过表达减少了血管平滑肌细胞的数量；(5)膜联蛋白A1的甲基化导致蛋白酶体依赖的降解；(6)铁络合作用抑制了PDGF诱导的人气道平滑肌细胞bcl-2和IL-13的mRNA表达上调。此外，用过敏原诱发哮喘的小鼠体内治疗可促进膜联蛋白A1的降解。这项拟议研究的基本原理是，一旦获得了调节气道平滑肌细胞生长和炎症反应的信号通路的知识，它将导致可用于预防和/或治疗哮喘的新策略。该应用的目标将通过追求三个特定的目标来实现：1)确定细胞信号媒介对人气道平滑肌细胞膜联蛋白A1的羰化作用的机制，2)确定蛋白质羰化在膜联蛋白A1降解机制中的作用，以及3)确定膜联蛋白A1在调节呼吸道平滑肌细胞生长和炎症反应中的作用。这项拟议的工作具有创新性，因为它将探索一种新的活性氧信号转导机制，并研究膜联蛋白A1在气道平滑肌调节细胞生长和炎症反应中的新作用。我期望包括PDGF和ET-1在内的哮喘介质能促进金属催化的膜联蛋白A1的羰化作用，这种作用通过涉及蛋白酶体的机制特异性地影响细胞生长、凋亡和炎症信号。这些结果将具有重大意义，因为它们有望为哮喘的预防和治疗干预提供新的药物。此外，这一结果将从根本上推动肺细胞生物学领域的发展。(摘要结束)