Role of Adenosine in Allergic Lung Disease

腺苷在过敏性肺病中的作用

• 批准号: 7822528
• 负责人: STEPHEN Lloyd TILLEY
• 金额: $ 1.72万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822528
• 关键词: Adenosine; Affect; Agonist; Allergens; Allergic; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Asthma; Bone Marrow; Bronchoconstriction; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Chronic Disease; Complex; Development; Disease; Exhalation; Functional disorder; Funding; G-Protein-Coupled Receptors; Gene Silencing; Genetically Modified Animals; Goals; Homeostasis; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Ligands; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Mus; Pathogenesis; Pathway interactions; Play; Protocols documentation; Purinergic P1 Receptors; Research; Role; Series; Signal Pathway; Signal Transduction; Sputum; Testing; Transfection; Translations; Umbilical Cord Blood; United States; airway hyperresponsiveness; airway inflammation; airway remodeling; allergic airway inflammation; antigen challenge; asthmatic airway; clinical application; desensitization; design; in vivo; mast cell; novel therapeutic intervention; programs; public health relevance; receptor; receptor coupling; receptor function; research study; small hairpin RNA; therapeutic target

DESCRIPTION (provided by applicant): Elevated adenosine levels in the lungs and exhaled breath of asthmatics, with further increases following antigen challenge, suggests that this ubiquitous mediator may contribute to the pathophysiology of asthma. Many of the effects of adenosine in the asthmatic lung are mast cell-dependent. Adenosine has both pro- and anti-inflammatory effects on mast cells, due to the expression of multiple adenosine receptors on the cell surface, each capable of activating very different intracellular signaling pathways. In this proposal we will test the hypothesis that both pro- and anti-inflammatory signals are transmitted to the mast cell by adenosine via the activation of distinct cell-surface receptors, and that engagement of these receptors by adenosine influences AHR, inflammatory cell influx, and airway remodeling. In aim 1 we will investigate the pro- inflammatory role of A3 receptors on mast cells in AHR, airway inflammation, and remodeling. In aim 2 we will investigate the capacity of agonist-induced activation of Gs-coupled adenosine receptors to limit AHR, airway inflammation, and remodeling. In aim 3 we will investigate constitutive activity of the A2B receptor. For all aims we will conduct in vitro experiments with human mast cells as well as mechanistic in vivo experiments using a series of models lacking adenosine receptors on mast cells. Completion of these aims will define pro- vs. anti-inflammatory signaling pathways on the mast cell, and identify the mechanisms by which adenosine- induced mast cell activation contributes to the cardinal features of asthma. PUBLIC HEALTH RELEVANCE. Asthma is a common chronic disease affecting approximately 10% of people in the United States. A better understanding of the inflammatory mediators involved in this disease, such as adenosine, will help identify new avenues of therapy, leading to better treatments for asthma.

描述（由申请人提供）：哮喘患者肺部和呼出气中的腺苷水平升高，并且在抗原攻击后进一步增加，表明这种普遍存在的介质可能有助于哮喘的病理生理学。腺苷对哮喘肺的许多作用是肥大细胞依赖性的。腺苷对肥大细胞具有促炎和抗炎作用，因为细胞表面表达多种腺苷受体，每种受体都能够激活非常不同的细胞内信号传导途径。在本提案中，我们将测试以下假设：促炎信号和抗炎信号均通过腺苷通过激活不同的细胞表面受体传递至肥大细胞，并且腺苷与这些受体的结合会影响 AHR、炎症细胞流入和气道重塑。在目标 1 中，我们将研究肥大细胞上 A3 受体在 AHR、气道炎症和重塑中的促炎作用。在目标 2 中，我们将研究激动剂诱导的 Gs 偶联腺苷受体激活限制 AHR、气道炎症和重塑的能力。在目标 3 中，我们将研究 A2B 受体的组成活性。为了实现所有目标，我们将使用人类肥大细胞进行体外实验，并使用一系列肥大细胞上缺乏腺苷受体的模型进行体内机制实验。完成这些目标将确定肥大细胞上的促炎与抗炎信号通路，并确定腺苷诱导的肥大细胞激活导致哮喘主要特征的机制。公共卫生相关性。哮喘是一种常见的慢性疾病，影响着大约 10% 的美国人。更好地了解与这种疾病有关的炎症介质（例如腺苷）将有助于确定新的治疗途径，从而更好地治疗哮喘。