AMSA: ALXR/FBR Mediated Signaling in Severe Asthma

AMSA：ALXR/FBR 介导的严重哮喘信号传导

• 批准号: 9058591
• 负责人: Elliot Israel
• 金额: $ 71.42万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-09 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058591
• 关键词: Accounting; Adrenal Cortex Hormones; Adult; Affect; Amyloid; Annexin A1; Annexins; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Biological Assay; Biological Models; Biological Process; Blood; Bronchoscopy; Child; Chronic Disease; Chronic Obstructive Airway Disease; Clinical; Data; Defect; Enrollment; FPR2 gene; Fibrosis; Goals; High Resolution Computed Tomography; In Vitro; Inflammation; Inflammatory; Leukotrienes; Ligands; Lipids; Lipoxins; Lung; Measures; Mediating; Mediator of activation protein; Molecular; Monitor; Morbidity - disease rate; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Process; Production; Progressive Disease; Proteins; Protocols documentation; Recruitment Activity; Regulation; Reporter; Research; Resolution; Risk; Sampling; Serum; Serum amyloid A protein; Signal Pathway; Signal Transduction; Specimen; Spirometry; Sputum; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Up-Regulation; X-Ray Computed Tomography; airway hyperresponsiveness; airway inflammation; airway remodeling; allergic airway inflammation; asthma inhaler; asthmatic; asthmatic patient; cohort; economic cost; experience; in vivo; insight; lipoxin A4; mortality; new therapeutic target; novel therapeutics; patient subsets; receptor; receptor expression; research study; respiratory; response; stem; support network

DESCRIPTION (provided by applicant): The proposed experiments will test the hypothesis that ALX axis dysregulation underlies persistent asthma and airway inflammation despite corticosteroid therapy in a cohort of patients with severe asthma. Lipoxin A4 (LXA4) is an anti-inflammatory and pro-resolving mediator that can interact with specific receptors (i.e., ALX/FPR2) to inhibit allergic airway inflammation and hyper-responsiveness in model systems. Severe asthma is characterized by decreased LXA4, suggesting that this condition may stem from a defect in counter-regulation. There are three additional ligands for ALX/FPR2 receptors, namely 15- epimer-LXA4, annexin A1 and serum amyloid A. All four ALX/FPR2 ligands are generated in asthma and together with ALX/FPR2 receptors comprise the "ALX axis." Of note, both protein ligands can be induced in vitro by corticosteroids, the most common asthma controller therapy, and unlike the other three ligands, serum amyloid a interactions with ALX/FPR2 paradoxically promotes inflammation, raising the possibility that a subset of patients with severe asthma may experience detriment rather than benefit from corticosteroids. Consistent with the requests of this RFA, we will recruit and characterize a cohort of severe and moderate adults and children with asthma and follow them for three years. The effects of corticosteroids on the ALX axis and the interaction with inflammatory and remodeling markers will be examined by obtaining blood and respiratory specimens before and 1 month after parenteral corticosteroids at enrollment. The clinical course of these subjects (particularly exacerbations and spirometry) will be monitored over 3 years followed by a repeat course of parenteral corticosteroids. The stability of the ALX axis phenotype post-corticosteroids will be assessed In blood and sputum, and its relationship to airway remodeling will be assessed by comparing high resolution CT scans performed (after corticosteroids) at the beginning and after 3 years in the study. To test our hypothesis, we propose two principal specific aims: 1. Determine the effect of corticosteroids on the ALX axis in severe and non-severe asthma, and 2. Define the relationship between the ALX aberrant phenotype and airway inflammation and progressive disease. The long-term goals for this research is to develop a comprehensive understanding of the perturbations in the ALX axis to the pathogenesis of severe asthma and the potential for components of this axis (lipoxins in particular) as possible novel therapeutic agents to alleviate severe asthma's excess morbidity.

描述（由申请人提供）：拟议的实验将验证在一组严重哮喘患者中，尽管皮质类固醇治疗，ALX轴失调是持续性哮喘和气道炎症的基础。脂素A4 （LXA4）是一种抗炎和促溶解介质，可与特定受体（即ALX/FPR2）相互作用，抑制模型系统中的过敏性气道炎症和高反应性。严重哮喘的特点是LXA4降低，这表明这种情况可能源于反调节缺陷。ALX/FPR2受体还有另外三种配体，即15-外周体lxa4、膜联蛋白A1和血清淀粉样蛋白a。所有四种ALX/FPR2配体都是在哮喘中产生的，它们与ALX/FPR2受体一起构成“ALX轴”。值得注意的是，这两种蛋白配体都可以通过皮质类固醇在体外诱导，皮质类固醇是最常见的哮喘控制疗法，与其他三种配体不同，血清淀粉样蛋白a与ALX/FPR2的相互作用矛盾地促进炎症，这增加了一种可能性，即一部分严重哮喘患者可能会因皮质类固醇而受到损害而不是受益。根据本RFA的要求，我们将招募一组患有重度和中度哮喘的成人和儿童，并对他们进行为期三年的随访。皮质类固醇对ALX轴的影响以及与炎症和重塑标志物的相互作用将通过在入组时获得静脉注射皮质类固醇前和后1个月的血液和呼吸标本来检查。这些受试者的临床病程（特别是病情加重和肺活量测定）将在3年内进行监测，然后再进行静脉注射皮质类固醇的重复疗程。将在血液和痰中评估皮质类固醇后ALX轴表型的稳定性，并通过比较研究开始时和研究3年后（皮质类固醇后）进行的高分辨率CT扫描来评估其与气道重塑的关系。为了验证我们的假设，我们提出了两个主要的具体目标：1 .确定皮质类固醇对重度和非重度哮喘患者ALX轴的影响；明确ALX异常表型与气道炎症及疾病进展的关系。本研究的长期目标是全面了解严重哮喘发病机制中ALX轴的扰动，以及该轴成分（特别是脂质）作为可能的新型治疗剂的潜力，以减轻严重哮喘的过度发病率。