NO-Modified Biomolecules and Pulmonary Signaling

NO 修饰的生物分子和肺部信号传导

• 批准号: 7657295
• 负责人: Andrew J Gow
• 金额: $ 34.76万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-11 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657295
• 关键词: A549; Ablation; Achievement; Acids; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affect; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Binding; Biological; Bleomycin; Blood Vessels; Bronchodilation; Cell physiology; Cells; Chemicals; Chemistry; Chronic lung disease; Cystic Fibrosis; Data; Development; Disease; Disease model; Enzyme Activation; Epithelial; Epithelial Cells; Equilibrium; Functional disorder; Genetic; Growth and Development function; Guanylate Cyclase; Heart; Heme; Immunity; Infection; Inflammation; Inflammatory; Injury; Lead; Lung; Lung diseases; Maintenance; Mediating; Metabolism; Modeling; Modification; Molecular; Morphogenesis; Mus; Nitrates; Nitric Oxide; Nitrosation; Oxidation-Reduction; Oxidoreductase; Pathogenesis; Pathology; Pathway interactions; Patients; Persistent Fetal Circulation Syndrome; Physiological; Physiology; Play; Pneumonia; Process; Production; Property; Pulmonary Emphysema; Pulmonary Pathology; Pulmonary Surfactant-Associated Protein D; Reaction; Research Project Grants; Role; Sepsis; Series; Signal Pathway; Signal Transduction; Signaling Molecule; System; Tail; Therapeutic; Therapeutic Intervention; Transplantation; Type II Epithelial Receptor Cell; Vasodilation; base; biological systems; chemokine; chemokine receptor; cytokine; design; in vivo Model; indium-bleomycin; inhaled nitric oxide; lung injury; macrophage; nitration; novel; novel therapeutic intervention; public health relevance; pulmonary arterial hypertension; pulmonary function; receptor expression

DESCRIPTION (provided by applicant): The central role that Nitric Oxide (NO) plays within pulmonary physiology is highlighted by the number of functions in which it plays a role including the maintenance of airway tone, blood vessel tone, inflammation, and even lung growth and development. In addition to these important physiological roles NO has also been implicated in a number of pulmonary diseases including ARDS, Asthma, and cystic fibrosis. As yet the molecular mechanisms by which this simple diatomic molecule can produce such a wide range of signals is unclear, furthermore, it is unclear how disruption of NO metabolism may play a role in pathology. It is the hypothesis of this proposal that the redox capabilities of NO allow it to generate a series of novel NO-modified biomolecules and that these molecules themselves have signaling properties. Furthermore, it is contended that disruption of the redox status of the lung alters the production of these molecules such that pulmonary signaling pathways are affected. Therefore the balance of the production of these molecules is critical to pulmonary physiology and their disruption could play a role in the pathogenesis of disease. This proposal seeks to examine such NO- modified biomolecules which have been demonstrated to possess signaling properties within pulmonary cells, namely S-nitrosylated Surfactant Protein D (SNO-SP-D) and nitrolinoleic acid (LNO2). The signaling properties of these molecules in epithelial and inflammatory cells will be examined. Previously it has been shown that NO metabolism is disrupted in a model of pulmonary disease, namely bleomycin-induced acute lung injury. Therefore the involvement of SNO-SP-D and LNO2 within this disease models will be examined. Utilization of mice in which nitrosothiol metabolism is impaired (GSNOR-/-) within this disease model will allow for more detailed examination of the involvement of NO-modified biomolecules in pulmonary pathophysiology. The proposal will therefore examine the following three specific aims: 1) To determine the effects of S-nitrosylation on SP-D signaling in pulmonary cells; 2) To determine the mechanisms of LNO2 on pulmonary cell signaling; 3) To examine the role of NO-modified biomolecules in pathology. Achievement of these aims will allow for a better understanding of how NO-modification of biomolecules plays a role in pulmonary pathophysiology. Ultimately this will allow for more focused NO-based therapeutics within the lung. PUBLIC HEALTH RELEVANCE. Pulmonary inflammation lies at the heart of many diseases that are currently on the rise such as asthma and emphysema. The chemical nitric oxide is an important part of inflammation and this research project will investigate how it controls cellular function within the lung. A greater understanding of these processes may lead to novel therapeutic approaches for inflammatory lung diseases.

描述（由申请人提供）：一氧化氮（NO）在肺部生理学中发挥的核心作用通过其所发挥的多种功能来强调，包括维持气道张力、血管张力、炎症，甚至肺部生长和发展。除了这些重要的生理作用之外，NO 还与许多肺部疾病有关，包括 ARDS、哮喘和囊性纤维化。迄今为止，这种简单的双原子分子产生如此广泛信号的分子机制尚不清楚，此外，还不清楚NO代谢的破坏如何在病理学中发挥作用。该提议的假设是，NO 的氧化还原能力使其能够产生一系列新型 NO 修饰的生物分子，并且这些分子本身具有信号传导特性。此外，有人认为，肺部氧化还原状态的破坏会改变这些分子的产生，从而影响肺部信号传导途径。因此，这些分子产生的平衡对于肺部生理学至关重要，它们的破坏可能在疾病的发病机制中发挥作用。该提案旨在检查此类 NO 修饰的生物分子，这些分子已被证明在肺细胞内具有信号传导特性，即 S-亚硝基化表面活性蛋白 D (SNO-SP-D) 和硝基亚油酸 (LNO2)。将检查这些分子在上皮细胞和炎症细胞中的信号传导特性。此前已有研究表明，在肺部疾病模型（即博来霉素诱导的急性肺损伤）中，NO 代谢受到破坏。因此，将检查 SNO-SP-D 和 LNO2 在该疾病模型中的参与情况。在该疾病模型中利用亚硝基硫醇代谢受损（GSNOR-/-）的小鼠将可以更详细地检查NO修饰的生物分子在肺部病理生理学中的参与情况。因此，该提案将研究以下三个具体目标： 1) 确定 S-亚硝基化对肺细胞 SP-D 信号传导的影响； 2) 确定LNO2对肺细胞信号传导的作用机制； 3) 检查NO修饰的生物分子在病理学中的作用。这些目标的实现将有助于更好地了解生物分子的 NO 修饰如何在肺部病理生理学中发挥作用。最终，这将允许在肺部进行更集中的基于一氧化氮的治疗。公共卫生相关性。肺部炎症是许多目前呈上升趋势的疾病的核心，例如哮喘和肺气肿。化学物质一氧化氮是炎症的重要组成部分，该研究项目将研究它如何控制肺内的细胞功能。对这些过程的更深入了解可能会带来治疗炎症性肺部疾病的新方法。