Role of Nitric Oxide in Radiation-Induced Lung Injury

一氧化氮在辐射引起的肺损伤中的作用

• 批准号: 8067815
• 负责人: RAMA MALAVIYA
• 金额: $ 14.22万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067815
• 关键词: Acute; Acute Lung Injury; Biomedical Research; Blood Vessels; Chronic; Development Plans; Disease; Drug Delivery Systems; Educational Activities; Effectiveness; Fibrosis; Generations; Goals; Health; Inflammation; Inflammatory; Injury; Instruction; Lung; Lung diseases; Measurement; Mediating; Mentors; Mus; NanoGel; Nitric Oxide; Pathogenesis; Pathology; Phase; Play; Pneumonia; Production; Pump; Radiation; Radiation Pneumonitis; Reactive Nitrogen Species; Research; Research Activity; Research Personnel; Rodent Model; Role; System; Testing; Toxic effect; Training; Treatment Protocols; abstracting; career development; effective therapy; experience; human NOS2A protein; inhibitor/antagonist; lung injury; mouse model; nitrosative stress; novel; targeted delivery

DESCRIPTION (provided by applicant): This mentored career development plan will help the P.I. re-enter the field of biomedical research after a 3- year hiatus, and will prepare her to conduct independent research focusing on pulmonary disease pathogenesis and treatment. The plan includes training in pulmonary toxicity, inflammation, and drug delivery through mentored research and educational activities. This experience will enable the P.I. to achieve her overall goal of becoming an independent investigator. The overall goal of the research is to elucidate inflammatory mechanisms mediating lung disease with a particular emphasis on the role of reactive nitrogen species (RONS) in disease pathogenesis. Although RONS have been shown to play a key role in acute lung injury and disease, their role in pneumonitis and consequent fibrosis is unknown and represents the focus of the research. To induce pneumonitis, a mouse model of radiation-induced lung injury will be used. The research plan will test the hypothesis that inhibiting production of RONS immediately following radiation exposure, while not reducing acute injury during the early latent phase of radiation induced injury, will significantly mitigate pneumonitis and consequent fibrosis. For these studies 1400W, a highly specific inhibitor of inducible nitric oxide synthase (iNOS), which has previously been shown to be effective in ameliorating acute lung injury in rodent models will be used. In aim 1, the efficacy of 1400W administered by Alzet micro-osmotic pumps in mitigating radiation induced iNOS activation and RONS generation will be assessed. Measurements will be made of markers of acute lung injury and oxidative/nitrosative stress. Aim 2 will be focused on assessing the effectiveness of 1400W in reducing consequent pneumonitis and fibrosis. In Aim 3, we will optimize a novel nanogel microparticle system to selectively deliver 1400W to the pulmonary vascular compartment of mice after radiation exposure. The results of these studies will provide important mechanistic information on the role of RONS in radiation induced lung injury and may provide clues on a novel efficacious treatment protocol for mitigating lung pneumonitis and fibrosis. RELEVANCE (See instructions): Pneumonitis and fibrosis consequent to acute lung injury are of major health concern. The identification of mechanisms leading to these pathologies and effective treatment protocols is key to minimizing chronic lung injury. (End of Abstract)

描述（由申请人提供）：该指导的职业发展计划将有助于P.I. 3年休息后，重新进入生物医学研究领域，并将为她做好准备，以进行独立研究，重点是肺部疾病发病机理和治疗。该计划包括通过指导的研究和教育活动进行肺毒性，炎症和药物输送的培训。这种经验将使P.I.为了实现她成为独立调查员的总体目标。该研究的总体目的是阐明介导肺部疾病的炎症机制，特别着重于反应性氮（RONS）在疾病发病机理中的作用。尽管已显示罗恩斯在急性肺损伤和疾病中起关键作用，但它们在肺炎中的作用，因此纤维化尚不清楚，代表了研究的重点。为了诱导肺炎，将使用辐射诱导的肺损伤的小鼠模型。该研究计划将检验以下假设：抑制辐射暴露后立即产生的RON的产生，同时在辐射诱发的损伤的潜在阶段不减少急性损伤，将大大减轻肺炎且随之而来的纤维化。对于这些研究，1400W是一种高度特异性的诱导一氧化氮合酶（INOS）的抑制剂，以前已证明将使用啮齿动物模型中的急性肺损伤有效。在AIM 1中，将评估Alzet微型渗透泵在缓解辐射诱导的iNOS激活和RONS产生的1400W的功效。将测量急性肺损伤和氧化/亚硝化应激的标记。 AIM 2将集中于评估1400W在减少随之而来的肺炎和纤维化的有效性上。在AIM 3中，我们将优化一种新型的纳米凝胶微粒系统，在辐射暴露后选择性地将1400W送到小鼠的肺部血管室。这些研究的结果将提供有关RON在辐射诱导的肺损伤中的作用的重要机械信息，并可能提供有关缓解肺部肺炎和纤维化的新型有效治疗方案的线索。 相关性（请参阅说明）：急性肺损伤导致的肺炎和纤维化是重大健康问题。鉴定导致这些病理的机制和有效的治疗方案是最大程度地减少慢性肺损伤的关键。 （抽象的结尾）