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: 8680347
• 负责人: Elliot Israel
• 金额: $ 70.82万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680347
• 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; Fibrosis; Goals; 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; Principal Investigator; Process; Production; Progressive Disease; Proteins; Protocols documentation; Recruitment Activity; Regulation; Relative (related person); Reporter; Research; Resolution; Risk; Sampling; Serum; Serum amyloid A protein; Signal Pathway; Signal Transduction; Specimen; Spirometry; Sputum; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; X-Ray Computed Tomography; airway hyperresponsiveness; airway inflammation; airway remodeling; allergic airway inflammation; asthma inhaler; cohort; economic cost; experience; in vivo; insight; lipoxin A4; mortality; new therapeutic target; novel therapeutics; receptor; receptor expression; research study; respiratory; response; stem

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. RELEVANCE: Severe asthma leads to daily symptoms with excess morbidity and mortality and a disproportionate share of the economic costs related to asthma. Despite the availability of many therapeutic options for asthma, these patients' asthma remains uncontrolled. In this proposal, we are investigating the possibility that dysregulation of a natural anti-inflammatory signaling pathway is related to the pathogenesis of severe asthma with a long- term goal of identifying novel therapeutic targets for this and other diseases of chronic inflammation.

描述（由申请方提供）：拟定的实验将检验以下假设：尽管在一组重度哮喘患者中进行了皮质类固醇治疗，但ALX轴失调仍是持续性哮喘和气道炎症的基础。脂氧素A4（LXA 4）是一种抗炎和促消退介质，其可以与特定受体（即，ALX/FPR 2）抑制模型系统中的过敏性气道炎症和高反应性。严重哮喘的特征是LXA 4减少，这表明这种情况可能源于反调节的缺陷。ALX/FPR 2受体还有三种额外的配体，即15-差向异构体-LXA 4、膜联蛋白A1和血清淀粉样蛋白A。所有四种ALX/FPR 2配体在哮喘中产生，并且与ALX/FPR 2受体一起构成“ALX轴”。“值得注意的是，这两种蛋白质配体都可以在体外由皮质类固醇诱导，这是最常见的哮喘控制剂治疗，与其他三种配体不同，血清淀粉样蛋白a与ALX/FPR 2的相互作用矛盾地促进炎症，提高了一部分严重哮喘患者可能会受到损害而不是从皮质类固醇中受益的可能性。 根据本RFA的要求，我们将招募和描述一组重度和中度哮喘成人和儿童，并随访三年。将通过在入组时在胃肠外皮质类固醇之前和之后1个月获得血液和呼吸道标本来检查皮质类固醇对ALX轴的影响以及与炎症和重塑标志物的相互作用。将在3年内监测这些受试者的临床病程（特别是急性加重和肺量测定），随后重复胃肠外皮质类固醇疗程。将在血液和痰液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; 2.明确ALX异常表型与气道炎症和疾病进展之间的关系。 本研究的长期目标是全面了解ALX轴对严重哮喘发病机制的扰动，以及该轴组分（特别是脂氧素）作为可能的新型治疗药物以减轻严重哮喘的过度发病率的潜力。 相关性：严重哮喘导致日常症状，发病率和死亡率过高，与哮喘相关的经济成本份额不成比例。尽管有许多治疗哮喘的选择，但这些患者的哮喘仍然不受控制。在这项提案中，我们正在研究天然抗炎信号通路的失调与严重哮喘的发病机制相关的可能性，长期目标是为这种疾病和其他慢性炎症疾病确定新的治疗靶点。