Dual Oxidase in Lung Epithelium

肺上皮中的双重氧化酶

• 批准号: 7742997
• 负责人: HORST B FISCHER
• 金额: $ 48.82万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-05 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742997
• 关键词: Acids; Address; Air; Alveolar; Alveolar Cell; Alveolus; Antioxidants; Area; Attention; Buffers; Candidate Disease Gene; Cell Differentiation process; Cell membrane; Cell model; Cells; Chronic lung disease; Culture Media; Cultured Cells; Data Analyses; Deferoxamine; Deposition; Disulfides; Environment; Epithelial; Epithelial Cells; Epithelium; Experimental Designs; Face; Fetal Lung; Figs - dietary; Gene Expression; Generations; Genes; Hormonal; Hormones; Host Defense; Human; Hydrogen Peroxide; In Vitro; Infection; Iron; Laboratories; Lead; Link; Lung; Measurement; Measures; Mediating; Methylene blue; NADPH Oxidase; Newborn Infant; Oxidants; Oxidases; Oxidation-Reduction; Patients; Physiological; Pregnancy; Premature Infant; Principal Investigator; Process; Production; Property; Protein Isoforms; Proteins; Protons; Public Health; Reaction; Reducing Agents; Regulation; Repression; Research; Role; Signal Transduction; Solutions; Sterility; System; Testing; Text; Therapeutic; Type II Epithelial Receptor Cell; alveolar epithelium; alveolar type II cell; antimicrobial; arm; ascorbate; cell growth regulation; clinically relevant; design; experience; high risk; improved; in vivo; killings; knock-down; lung development; novel; overexpression; programs; promoter; protein expression; research study; response; tissue culture

DESCRIPTION (provided by applicant): Oxidant production by the lung alveolar epithelium has been little investigated despite its potential roles in alveolar host defense and cell signaling. Our preliminary studies in a cultured human lung cell model show that hormone-induced type II cell differentiation is associated with increased expression of the NADPH oxidase isoform dual oxidase 1 (DUOX1) and its maturation factor DUOXA1. Similarly, DUOX protein expression was found to be upregulated in vivo during late gestation in human lung. We also found a strong correlation between expression of DUOX1 and the production of hydrogen peroxide and acid by alveolar cells. To date, DUOX1 is the only known mechanism to control the regulated release of oxidants by the alveolar epithelium. We hypothesize that DUOX1 and DUOXA1 are coordinately up-regulated during differentiation of alveolar type II cells, which increases oxidant and acid production by the alveolar epithelium and contributes to host defense and cellular signaling in the newborn lung. The proposed studies will define the regulated expression of DUOX1 and DUOXA1 in a unique primary cultured cell model of alveolar epithelial cells, and help clarify the function and role of DUOX1 in alveolar innate defense, redox regulation, and cellular signaling. Aim 1 seeks to determine the shared promoter and the regulated expression of DUOX1 and DUOXA1 during differentiation of human fetal lung type II cells. Aim 2 will determine the effects of expression of DUOX1 on the production of hydrogen peroxide and protons, on bacterial killing, and on alveolar epithelial function. Aim 3 will establish a controlled over-expression cell model to study the effects of Duox1 on cellular signaling, gene expression, and alveolar function. The proposed study will be a collaborative effort between two laboratories with experience in lung development/gene expression (Ballard/Gonzales) and the biophysical properties of lung epithelial cell membranes (Fischer/Illek); it will be the first study to provide information regarding regulation and function of DUOX1 in alveolar epithelial cells. This research has physiological significance related to the sterility of the alveolar air space and clinical relevance for understanding deficiencies in host defense and epithelial function in premature infants and patients with chronic lung diseases. Project Narrative Premature infants are at high risk for lung infections, an important area of public health. This research investigates a novel area of lung anti-microbial defense and will provide new information that may lead to therapeutic application.

描述（由申请人提供）：尽管肺泡上皮产生的氧化剂在肺泡宿主防御和细胞信号传导中具有潜在作用，但对其产生的研究却很少。我们在培养人肺细胞模型中的初步研究表明，激素诱导的 II 型细胞分化与 NADPH 氧化酶亚型双氧化酶 1 (DUOX1) 及其成熟因子 DUOXA1 的表达增加有关。类似地，在人肺的妊娠晚期期间，体内发现 DUOX 蛋白的表达上调。我们还发现 DUOX1 的表达与肺泡细胞产生过氧化氢和酸之间存在很强的相关性。迄今为止，DUOX1 是唯一已知的控制肺泡上皮调节氧化剂释放的机制。我们假设 DUOX1 和 DUOXA1 在 II 型肺泡细胞分化过程中协同上调，这增加了肺泡上皮的氧化剂和酸的产生，并有助于新生肺中的宿主防御和细胞信号传导。拟议的研究将定义 DUOX1 和 DUOXA1 在肺泡上皮细胞的独特原代培养细胞模型中的调节表达，并有助于阐明 DUOX1 在肺泡先天防御、氧化还原调节和细胞信号传导中的功能和作用。目标 1 旨在确定人胎肺 II 型细胞分化过程中 DUOX1 和 DUOXA1 的共享启动子和受调节的表达。目标 2 将确定 DUOX1 表达对过氧化氢和质子的产生、细菌杀灭以及肺泡上皮功能的影响。目标3将建立受控过度表达细胞模型，以研究Duox1对细胞信号传导、基因表达和肺泡功能的影响。拟议的研究将是两个在肺发育/基因表达（Ballard/Gonzales）和肺上皮细胞膜生物物理特性（Fischer/Illek）方面拥有丰富经验的实验室之间的合作成果；这将是第一项提供有关肺泡上皮细胞中 DUOX1 调节和功能信息的研究。这项研究对于肺泡气腔的无菌性具有生理意义，对于了解早产儿和慢性肺病患者的宿主防御和上皮功能缺陷具有临床意义。项目叙述 早产儿肺部感染的风险很高，这是公共卫生的一个重要领域。这项研究研究了肺部抗微生物防御的新领域，并将提供可能导致治疗应用的新信息。