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，影响了十二分之一的人。在上一个奖项期间，我们的项目和核心的研究确定了气道注射和重塑哮喘的粘膜机制。我们在该程序的续签中的总体目标是揭示气道上皮细胞获得促炎功能的基本机制，而气道平滑肌细胞采用了超额收缩和重塑表型，以便我们可以应用发现的发现更有效和靶向性疗法。我们假设粘膜上皮平滑的肌肉耦合单元会引发气道感染，过度反应性和重塑。为了检验这一假设，我们的科学家团队拥有战略性的创新和机械项目，这些项目由强大的核心支持，这些核心使用尖端的技术研究主要气道细胞，有机培养物，精确切割肺切片，鼠类遗传模型和哮喘患者的临床研究。项目1是一个延续，并研究了精氨酸代谢，通过精氨酸酶和一氧化氮（NO）合酶的激活如何调节气道上皮细胞代谢以及上皮细胞细胞因子和粘液产生。项目2是一个延续和建议，以确定[[气道上皮和平滑肌相互作用]]导致哮喘中病理透明质酸基质的机制。作为一个合作的新项目开发，项目3研究了对气道上皮功能和平滑肌肉反应至关重要的控制疾病蛋白成熟的机制，例如[[探索探索药物可溶性鸟苷酸环化酶活化剂作为支气管扩张剂的新途径。]]项目4是一个新的项目，这是一个新的项目，这是一个新的项目，这是一个新的项目，并通过kitysy inty nate nate nate natery nity nity nity nity nity nity nity nity nity nity nity nity nity n n n n n n n n n n n n n n n n n n an n n n and n n n n n n n n n n n n n n n n n n an n n n an n n n n n an n n n n an n and n n n n and n n and naty。核心B提供了哮喘表型和临床样本。在技术上挑战和专业测定法和原代细胞培养的专门测定得到了新的CoreC。使用一般修改的小鼠的哮喘模型由CoreD提供。我们的研究人员提供了完善的产品协作，并在程序协同和相互作用上大写了。在该计划的每个步骤中，我们综合的多学科团队的重点是在不久的将来应用发现，以使哮喘患者更好，更安全。