Role of Adenosine in Allergic Lung Disease

腺苷在过敏性肺病中的作用

基本信息

批准号：
7667775
负责人：
STEPHEN Lloyd TILLEY
金额：
$ 37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7667775
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

项目摘要

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）：在抗原挑战之后进一步增加，肺部和呼出的哮喘呼吸呼吸升高表明，这种无处不在的介体可能有助于哮喘的病理生理学。腺苷在哮喘肺中的许多作用都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，这是由于细胞表面上多种腺苷受体的表达，每种腺苷受体能够激活非常不同的细胞内信号通路。在该提案中，我们将检验以下假设：促炎和抗炎信号都通过腺苷通过腺苷通过激活不同的细胞表面受体传播到肥大细胞，以及腺苷通过腺苷影响AHR，炎症细胞涌入和气道重塑的这些受体的参与。在AIM 1中，我们将研究A3受体在AHR，气道炎症和重塑中的炎症作用。在AIM 2中，我们将研究激动剂诱导的GS耦合腺苷受体激活的能力，以限制AHR，气道炎症和重塑。在AIM 3中，我们将研究A2B受体的组成型活性。对于所有目的，我们将使用一系列在肥大细胞上缺乏腺苷受体的模型对人类肥大细胞进行体外实验以及体内实验的机械实验。这些目标的完成将定义肥大细胞上的抗炎信号通路，并确定腺苷诱导的肥大细胞激活有助于哮喘的基本特征的机制。公共卫生相关性。哮喘是一种常见的慢性疾病，影响了美国约10％的人。更好地了解参与该疾病的炎症介质（例如腺苷）将有助于确定治疗的新途径，从而为哮喘提供更好的治疗方法。