NO-Modified Biomolecules and Pulmonary Signaling

NO 修饰的生物分子和肺部信号传导

基本信息

批准号：
8707538
负责人：
Andrew J Gow
金额：
$ 33.65万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-11 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707538
关键词：
Adoptive Transfer Adult Respiratory Distress Syndrome Alveolar Alveolar Macrophages Asthma Attenuated Biological Bleomycin Blood Vessels Breathing Cells Chronic Cystic Fibrosis Data Enzymes Epithelial Epithelium Equilibrium Fibrosis Funding Generations Genes Glutathione Growth and Development function Heterotrimeric GTP-Binding Proteins Inflammation Inflammatory Inflammatory Response Injury Knock-out Knowledge Laboratories Lung Lung diseases Lymphocyte Measures Mediating Metabolism Modeling Modification Molecular Molecular Weight Mus NOS2A gene Nitric Oxide Nitric Oxide Synthase Organ Outcome Oxidants Oxidoreductase Pathogenesis Pathology Patients Phase Phenotype Physiological Physiology Play Pneumonia Process Protein Isoforms Proteins Proteome Pulmonary Pathology Pulmonary Surfactant-Associated Protein D Recruitment Activity Resolution Respiratory System Role S-Nitrosoglutathione S-Nitrosothiols Signal Transduction Signaling Molecule Signaling Protein Source Sulfhydryl Compounds Surface Tail Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Xenobiotics design extracellular genetic regulatory protein human NOS2A protein inflammatory marker inhaled nitric oxide inhibitor/antagonist lung injury macrophage novel persistent pulmonary hypertension public health relevance pulmonary function repaired response response to injury therapeutic target

项目摘要

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 maintenace of ariway 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. In inflammation, the most important source of NO is the inducible form of the enzyme iNOS. A key downstream effect of iNOS-derived NO is S-nitrosylation of thiol residues to form S-nitrosothiol (SNO). We hypothesize that, by SNO modification of different target proteins, iNOS-derived NO can regulate both the pro-inflammatory and the resolution responses to injury. We have constructed a model in which NO produced early in the inflammatory response within resident macrophages serves to S-nitrosylate extracellular targets, such as Surfactant Protein-D (SP-D); while later in the response, with increasing fluxes of NO and the generation of other oxidants, intracellular S-nitrosylation of targets, such as NF-?B, promotes resolution and repair. We plan to investigate how the presence of iNOS and the SNO-degrading enzyme, GSNOR, in resident and recruited macrophages alters the outcome of bleomycin-mediated lung injury. We have chosen this injury model as it has both an inflammatory and a resolution/repair phase and is therefore ideal for examining our hypothesis. In the first aim differential expression of these enzymes that balance the S-nitrosylation response will be achieved with the use of adoptive transfer. We will determine the effects of loss of iNOS and GSNOR within resident and recruited macrophages at the molecular, cellular, and organ function level. In the second aim, we will examine how we can use knowledge of the signaling mechanisms of a particular SNO target protein, SP-D, to either accentuate or exacerbate bleomycin-mediated lung injury. These studies use state of the art techniques to determine how NO can signal through S-nitrosylation of different target proteins and may provide novel avenues for therapeutic design.

描述（由申请人提供）：一氧化氮（NO）在肺部生理学中发挥作用的核心作用是由其在作用的功能数量中强调的，包括Ariway张力的维护，血管张力，炎症，甚至肺部生长和发育。除了这些重要的生理作用外，NO还与许多肺部疾病有关，包括ARDS，哮喘和囊性纤维化。到目前为止，这种简单的双原子分子可以产生如此广泛的信号的分子机制尚不清楚，此外，尚不清楚无代谢的破坏如何在病理学中起作用。在炎症中，NO的最重要来源是酶iNOS的诱导形式。 iNOS衍生的NO的关键下游效应是硫醇残基形成S-硝基硫醇（SNO）的S-亚硝基化。我们假设，通过对不同靶蛋白的SNO修改，iNOS衍生的NO可以调节促炎和分辨率对损伤的反应。我们已经构建了一个模型，该模型在居民巨噬细胞内的炎症反应早期没有产生，可用于S-硝基盐外细胞外靶标，例如表面活性剂蛋白-D（SP-D）；在响应中后期，随着NO的通量增加和其他氧化剂的产生，靶标的细胞内S-硝基化（例如NF-？b）促进了分辨率和修复。我们计划调查iNOS和SNO降解酶，GSNOR在居民和招募的巨噬细胞中如何改变博来霉素介导的肺损伤的结果。我们选择了这种伤害模型，因为它具有炎症和分辨率/修复阶段，因此是检查我们的假设的理想选择。在这些酶的第一个目标差异表达中，将通过使用过转移来达到S-硝基化反应的平衡。我们将确定居民内iNOS和GSNOR丢失的影响，并在分子，细胞和器官功能水平下募集巨噬细胞。在第二个目标中，我们将研究如何利用特定SNO靶蛋白SP-D的信号传导机制的知识来突出或加剧博来霉素介导的肺损伤。这些研究使用艺术技术来确定如何通过不同靶蛋白的S-硝基化信号，并可能为治疗设计提供新的途径。