Lipidomic and Transcriptome Signatures in Aspirin-Exacerbated Respiratory Disease

描述(由申请人提供)：阿司匹林加重的呼吸系统疾病(AERD)的特征是持续的上、下呼吸道慢性炎症，导致慢性鼻窦炎、鼻息肉和哮喘。当AERD患者服用阿司匹林或其他环氧合酶1抑制剂时，他们的鼻窦炎会急性恶化，并伴有可能危及生命的急性支气管收缩。AERD影响了约10%的成人哮喘患者，但其根本机制仍不清楚。在生化方面，AERD的特征是二十烷类化合物的生成和功能异常。在基线时，半胱氨基白三烯的生成增加，并在抑制环氧合酶1的反应中进一步释放。对白三烯E4的支气管收缩反应增强。AERD患者的呼吸道组织显示1型半胱氨酸白三烯受体表达增加，环氧合酶2和前列腺素E2的2型受体表达减弱。我们的初步数据表明，AERD患者的呼吸组织强烈地将花生四烯酸代谢成至少三种主要代谢物，其中一种是我们在15-HETE确定的；另外两种代谢物尚未被鉴定。这一显着异常的二十烷基类化合物表明，以前未被认识的花生四烯酸代谢产物参与了AERD的病理生物学。AERD中二十烷样物质的产生和反应性的异常缺乏连贯的解释，最先进的技术也没有应用于他们的研究。我们建议使用两种最先进的技术来解决AERD的基本机制。我们将使用顺序液相色谱/串联质谱仪对AERD患者鼻息肉组织产生的脂质介质进行全面分析，并将其与阿司匹林耐受的慢性鼻窦炎哮喘患者进行比较。我们将结合全基因组对来自同一个体的鼻息肉的转录组进行分析。这一结合的方法将使我们能够评估AERD的基因表达特征，以丰富作为炎症过程和脂质介质生成异常基础的已定义的功能基因网络。成功将导致我们对AERD的理解取得重大突破，将刺激AERD新疗法的开发，并将使依赖于潜在危险的体内阿司匹林激发试验的新型诊断工具的开发成为可能。公共卫生相关性：哮喘是一种常见疾病，影响着美国约15%的人口，大约十分之一的成人哮喘患者在服用阿司匹林或类似的止痛药时会发生危及生命的哮喘发作。这些人患有衰弱的鼻窦病和严重的哮喘。这项建议的目的是使用最先进的分析技术来分析阿司匹林加重的呼吸系统疾病患者呼吸道中产生的脂质介质和表达的基因，以便为这种疾病的机制、诊断和治疗提供关键的新见解。

DESCRIPTION (provided by applicant): Aspirin-exacerbated respiratory disease (AERD) is characterized by persistent chronic inflammation of the upper and lower airways leading to chronic rhinosinusitis, nasal polyposis, and asthma. When individuals with AERD ingest aspirin or other inhibitors of cyclooxygenase 1 they develop acute worsening of their rhinosinusitis accompanied by acute bronchoconstriction that may be life-threatening. AERD affects ~10% of adults with asthma, yet the fundamental underlying mechanisms remain unknown. Biochemically, AERD is characterized by abnormalities in eicosanoid generation and function. There is increased generation of cysteinyl leukotrienes at baseline and further release in response to inhibition of cyclooxygenase 1. The bronchoconstrictor response to leukotriene E4 is increased. Respiratory tissues of individuals with AERD show increased expression of the type 1 cysteinyl leukotriene receptor and diminished expression of cyclooxygenase 2 and the type 2 receptor for prostaglandin E2. Our preliminary data indicate that respiratory tissue from individuals with AERD avidly metabolize arachidonic acid to at least three major metabolites, one of which we identified at 15-HETE; the other 2 metabolites have not been identified. This strikingly abnormal eicosanoid profile indicates the involvement of previously unrecognized arachidonate metabolites in the pathobiology of AERD. The abnormalities in eicosanoid generation and responsiveness in AERD lack a coherent explanation, and state-of-the-art technology has not been applied to their investigation. We propose to use two state-of-the-art techniques to address the fundamental mechanisms of AERD. We will use sequential liquid chromatography/tandem mass spectrometry to provide a comprehensive analysis of the lipid mediators generated by nasal polyp tissue from individuals with AERD compared to aspirin-tolerant asthmatics with chronic rhinosinusitis. We will combine this with genome-wide analysis of the transcriptome of nasal polyps from the same individuals. This combined approach will allow us to evaluate the gene expression signature in AERD for enrichment of defined functional gene networks that underlie the inflammatory process and the abnormalities in lipid mediator generation. Success will lead to a significant break-through in our understanding of AERD, will spur the development of new treatments for AERD, and will allow the development of novel diagnostic tools that do rely on potentially dangerous in vivo provocation tests with aspirin. PUBLIC HEALTH RELEVANCE: Asthma is a common disease that affects about 15% of the population of the United States, and about one in every ten adults with asthma develops life-threatening attacks of asthma when they ingest aspirin or similar analgesics. These individuals suffer from debilitating sinus disease and severe asthma. The aim of this proposal is to use state-of-the art analyses of the lipid mediators that are generated and the genes that are expressed in the airways of individuals with aspirin-exacerbated respiratory disease in order to provide key new insights into the mechanisms of this disease, its diagnosis, and its treatment.