Role of Adenosine in Allergic Lung Disease

腺苷在过敏性肺病中的作用

• 批准号: 6729839
• 负责人: STEPHEN Lloyd TILLEY
• 金额: $ 18.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729839
• 关键词: adenosine; asthma; cell surface receptors; cell type; chronic obstructive pulmonary disease; disease /disorder model; gene targeting; genetically modified animals; inflammation; laboratory mouse; mast cell; neural transmission; neuroimmunomodulation; ovalbumin; pathologic process; plethysmography; protein structure function; purinergic receptor; receptor expression; respiratory airway pressure; respiratory function; tissue /cell culture

DESCRIPTION (provided by applicant): Adenosine has become increasingly recognized as a contributor to the pathogenesis of asthma through its effects on airway tone and airway inflammation. Adenosine acts through four distinct cell surface receptors, however, the specific receptor(s) through which adenosine acts to contribute to asthma pathogenesis is largely unknown. The hypothesis that will be tested in this proposal is that adenosine contributes to both the airway tone and airway inflammation in asthma through identifiable cell surface receptors, and that inactivation of these receptors will influence the degree of bronchoconstriction and airway inflammation. We have chosen to test the hypothesis-utilizing mouse in which each adenosine receptor has been inactivated by gene targeting. We propose to carry out three specific aims to test our hypothesis. First, we will determine the adenosine receptors and cell types mediating the bronchoconstrictor effects of adenosine in the murine airway. Second, we will determine the adenosine receptors responsible for the pro- and anti-inflammatory effects of adenosine in allergic lung inflammation using the ovalbumin asthma model. Finally, we will determine the specific cell types contributing to adenosine-induced modulation of allergic inflammation. The full therapeutic potential of adenosine receptor blockade has not been exploited due to this complex physiology involving multiple adenosine receptors with diverse and sometimes opposing physiological effects. This proposal seeks to better define the pathophysiology of adenosine, acting through each receptor, in an animal model of asthma, so that a more rational exploitation of these receptors with selective pharmacological tools can be investigated in patients with asthma.

描述（由申请人提供）：腺苷通过其对气道音调和气道炎症的影响而越来越被公认为是哮喘发病机理的原因。 腺苷通过四个不同的细胞表面受体起作用，但是，腺苷通过这些特定受体有助于哮喘发病机理，这在很大程度上尚不清楚。 该提案中将检验的假设是，腺苷通过可识别的细胞表面受体在哮喘中促进气道张力和气道炎症，并且这些受体的失活将影响支气管收缩和气道炎症的程度。 我们选择测试耗尽假设的小鼠，其中每个腺苷受体被基因靶向灭活。 我们建议执行三个特定的目标来检验我们的假设。 首先，我们将确定腺苷受体和细胞类型介导鼠气中腺苷的支气管收缩作用。 其次，我们将确定使用卵巢蛋白哮喘模型来确定腺苷对腺苷在过敏性肺部炎症中的促炎和抗炎作用。 最后，我们将确定导致腺苷诱导的过敏性炎症调节的特定细胞类型。 由于这种复杂的生理学涉及多种具有多种生理作用的腺苷受体，因此尚未利用腺苷受体阻滞的全部治疗潜力。 该提案旨在更好地定义腺苷的病理生理，在每个受体中，在哮喘动物模型中作用于每个受体，以便可以在哮喘患者中对使用选择性药理工具的这些受体进行更合理的剥削。