Pathobiology of Asthma

哮喘病理学

• 批准号: 9015466
• 负责人: Serpil C. Erzurum
• 金额: $ 166.44万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015466
• 关键词: Address; Adrenal Cortex Hormones; Adrenergic Agonists; Adrenergic Receptor; Affect; Agonist; Allergens; American; Animal Model; Antiinflammatory Effect; Arginine; Asthma; Award; Biological Assay; Bronchoconstriction; Bronchodilation; Bronchodilator Agents; Caring; Cell physiology; Cells; Cellular Metabolic Process; Chronic Disease; Clinical Research; Collaborations; Coupled; Cytoskeleton; Development; Epithelial; Epithelial Cells; Exhalation; FDA approved; Figs - dietary; Functional disorder; Future; Gene Expression; Genetic Models; Goals; Heme; Hemeproteins; Human; Hyaluronan; Individual; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Leukocytes; Lung; Maintenance; Mediating; Metabolic Pathway; Metabolism; Modeling; Mucous body substance; Mus; NOS2A gene; Nitric Oxide; Nitric Oxide Synthase; Obstruction; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient Care; Patients; Phenotype; Phosphotransferases; Primary Cell Cultures; Process; Production; Research; Research Personnel; Research Project Grants; Role; Sampling; Scientific Advances and Accomplishments; Scientist; Slice; Smooth Muscle; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; Symptoms; Technology; Testing; United States; Vascular Diseases; Work; airway epithelium; airway hyperresponsiveness; airway inflammation; airway remodeling; amino acid metabolism; arginase; asthmatic; asthmatic airway; asthmatic patient; base; beta-adrenergic receptor; clinical phenotype; cytokine; effective therapy; extracellular; innovation; multidisciplinary; novel; novel strategies; programs; research study; respiratory smooth muscle; response; standard care; success; targeted treatment; therapeutic development; transcription factor

DESCRIPTION (Provided by applicant): Asthma is one of the most common chronic diseases in the United States, affecting approximately one in 12 people. Over the previous award period, research by our Projects and Cores identified mucosal mechanisms underlying airway inflammation and remodeling of asthma. Our overarching goal in this renewal of the Program is to uncover the fundamental mechanisms by which airway epithelial cells acquire pro-inflammatory functions and airway smooth muscle cells take on a hypercontractile and remodeling phenotype so that we can apply the discoveries to develop more effective and targeted therapies for asthma patients. We hypothesize that the mucosal epithelial-smooth muscle coupled unit initiates and perpetuates airway inflammation, hyper-reactivity and remodeling. To test this hypothesis, our team of scientists has strategized innovative and mechanistic Projects that are supported by powerful Cores that use cutting-edge technology to study primary airway cells, organotypic cultures, precision cut lung slices, murine genetic models and clinical study of asthma patients. Project 1 is a continuation and investigates how the activation of arginine metabolism, through arginase and nitric oxide (NO) synthases, regulates airway epithelial cell metabolism and epithelial cell cytokine and mucus production. Project 2 is a continuation and proposes to identify the mechanisms by which [[airway epithelium and smooth muscle interactions]] lead to a pathologic hyaluronan matrix in asthma. Developed as a collaborative new project, Project 3 investigates the mechanisms by which NO controls hemeprotein maturation important to airway epithelial function and smooth muscle reactivity, e.g. soluble guanylate cyclase, and [[explores pharmacologic soluble guanylate cyclase activators as a new pathway for bronchodilation.]] Project 4 is a new project made possible by Program-supported collaborations and investigates the resensitization of ß-adrenergic receptors in the asthmatic airway through kinase pathways that are regulated by nitrosylation. Asthma phenotyping and clinical samples are made available by Core B. Technically challenging and specialized assays for NO and primary cell cultures are supported by a new Core C. Models of asthma using genetically modified mice are provided by Core D. Our investigators have well-established productive collaborations and capitalize on Program synergies and interactions that assure the Program success. The focus of our integrated multidisciplinary team at every step of the Program is to apply discoveries for the better and safer care of asthmatic patients in the very near future.

描述（由申请人提供）： 哮喘是美国最常见的慢性疾病之一，影响大约十二分之一的人。在上一个奖项期间，我们的项目和核心研究确定了气道炎症和哮喘重塑的粘膜机制。该计划的目的是揭示气道上皮细胞获得促炎功能和气道平滑肌细胞呈现过度收缩和重塑表型的基本机制，以便我们能够应用这些发现来开发更有效和有针对性的药物。我们率先提出粘膜上皮-平滑肌单元耦合引发并维持气道炎症、高反应性和重塑，为了检验这一假设，我们的科学家团队制定了由强大核心支持的创新和机械项目。使用尖端技术研究原代气道细胞、器官型培养物、精密切割肺切片、小鼠遗传模型和哮喘患者的临床研究是项目1的延续和调查。精氨酸代谢如何通过精氨酸酶和一氧化氮 (NO) 合成酶的激活来调节气道上皮细胞代谢以及上皮细胞细胞因子和粘液的产生 项目 2 是项目 2 的延续，旨在确定[[气道上皮和平滑肌的机制。相互作用]] 导致哮喘中的病理性透明质酸基质作为一个合作新项目开发，项目 3 研究 NO 控制血红素蛋白的机制。成熟对气道上皮功能和平滑肌反应性很重要，例如可溶性鸟苷酸环化酶，并且[[探索药理学可溶性鸟苷酸环化酶激活剂作为支气管扩张的新途径。]]项目 4 是一个由计划支持的合作实现的新项目，并研究了通过激酶途径使哮喘气道中的 β-肾上腺素受体重新变得敏感，而激酶途径受以下因素调节亚硝基化分析和临床样本由 Core B 提供。新的 Core C 支持技术上具有挑战性的专门化 NO 和原代细胞培养物测定。使用转基因小鼠的哮喘模型由 Core D 提供。我们的研究人员拥有良好的研究成果。 -建立富有成效的合作并利用计划的协同作用和互动来确保计划的成功，我们的综合多学科团队在计划的每一步的重点是应用发现，为哮喘患者提供更好、更安全的护理。不久的将来。