SPLUNC1 in Severe Asthma

SPLUNC1 治疗严重哮喘

• 批准号: 8851736
• 负责人: Hong W Chu
• 金额: $ 40.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851736
• 关键词: Abbreviations; Accounting; Acute; Adrenal Cortex Hormones; Adult; Affect; Allergens; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Attenuated; Bacteria; Binding; Biological Markers; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cell Culture Techniques; Chemotactic Factors; Child; Clinical; Collaborations; Collection; Data Coordinating Center; Development; Disease; Disease Progression; Down-Regulation; Elements; Eotaxin; Epithelial; Epithelial Cells; Exhalation; Funding; Gene Expression Profile; Genetic Variation; Goals; Health Care Costs; Host Defense; Human; IL8 gene; Immunity; Individual; Infection; Intercellular adhesion molecule 1; Interleukin-13; Lead; Life; Link; Liquid substance; Longitudinal Studies; Lung; Mediating; Minority; Morbidity - disease rate; Mucous body substance; Mus; Nasal Epithelium; National Heart, Lung, and Blood Institute; Natural History; Nitric Oxide; Nose; Palate; Pathogenesis; Patients; Phenotype; Predisposition; Procedures; Property; Proteins; Protocols documentation; Research; Research Personnel; Rhinovirus; Role; SERPINB2 gene; Sampling; Severities; Single Nucleotide Polymorphism; Site; Sputum; Symptoms; Testing; Time; Transgenic Organisms; United States National Institutes of Health; Viral; Viral Physiology; Virus; Virus Diseases; abstracting; airway epithelium; airway inflammation; allergic airway inflammation; asthma prevention; asthmatic; asthmatic airway; asthmatic patient; effective therapy; eosinophil; eosinophilic inflammation; improved; in vivo; minimally invasive; mortality; neutrophil; novel; novel therapeutic intervention; periostin; prevent; programs; public health relevance; pulmonary function; receptor; secretory protein; surfactant

 DESCRIPTION (provided by applicant): Severe asthma afflicts about 10% of asthma patients, but utilizes 30 to 50% asthma-associated healthcare costs. It is imperative to understand the mechanisms by which severe asthma in particular acute exacerbation develops. To improve the understanding of severe asthma and to develop better treatments, for the last 14 years, NIH/NHLBI has funded the Severe Asthma Research Program (SARP), the world's most comprehensive study of adults and children with severe asthma that are currently performed at seven leading asthma research sites in the US. The current SARP (SARP3) has started collecting upper and lower airway samples to study severe asthma pathobiology. This offers an unprecedented opportunity to further our understanding of natural history of asthma, disease progression and new therapeutic interventions. However, SARP3 protocols do not include the collection of minimally invasive nasal airway epithelial cells, an approach that can be repeated longitudinally to study asthma pathogenesis. Thus, we propose a time-sensitive study by using nasal airway epithelial cells to determine the role of a novel host defense protein SPLUNC1 in severe asthma. Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is a secretory protein from large airway (nasal, tracheal and bronchial) epithelial cells and is abundant in the epithelial lining fluid of healthy individuals. Through collaboration with SARP investigators, we identified SPLUNC1 as one of the most significantly decreased proteins in bronchoalveolar lavage fluid samples from severe asthmatics. We have found that SPLUNC1 exerts host defense functions against human rhinoviruses and bacteria involved in asthma exacerbations - a leading cause of morbidity, mortality and health care costs in asthma. We discovered SPLUNC1-deficient mice have exaggerated airway allergic inflammation following allergen challenges (e.g., eosinophils and mucus, relevant to asthma exacerbations). Moreover, transgenic over-expression of human SPLUNC1 in mouse airways attenuates allergen-induced eosinophilic inflammation. However, the role of SPLUNC1 in human severe asthma is unclear. We hypothesize that down-regulation of SPLUNC1 in asthmatic airways increases rhinovirus infection and associated asthma exacerbations contributing to asthma severity. In continuing collaboration with SARP and its data coordination center, we will define the role of SPLUNC1 in severe asthma phenotypes. Furthermore, we will team up with 4 SARP sites to collect brushed live nasal airway epithelial cells from asthmatic children and adults during asthma exacerbations to determine if lower baseline SPLUNC1 levels predispose the patients to rhinovirus infection and asthma exacerbations. Finally, we will mechanistically determine SPLUNC1's anti-viral and anti-inflammatory functions that are critical to the prevention of asthma exacerbations. Successful completion of this time-sensitive ancillary R01 proposal will guide use of SPLUNC1 as a biomarker and a new therapy to prevent or treat acute asthma exacerbations.

 描述（由申请人提供）：严重哮喘困扰着大约 10% 的哮喘患者，但占用了 30% 至 50% 的哮喘相关医疗费用。为了提高对严重哮喘（特别是急性加重）的发病机制的了解，势在必行。为了解决严重哮喘的问题并开发更好的治疗方法，在过去 14 年里，NIH/NHLBI 资助了严重哮喘研究计划 (SARP)，这是世界上最全面的研究计划目前在美国七个领先的哮喘研究中心进行的针对患有严重哮喘的成人和儿童的研究当前的 SARP (SARP3) 已开始收集上呼吸道和下呼吸道样本以研究严重哮喘病理学，这为进一步开展我们的研究提供了前所未有的机会。然而，SARP3 方案不包括微创鼻气道上皮细胞的收集，这是一种可以纵向重复研究哮喘发病机制的方法。敏感的通过使用鼻气道上皮细胞来确定新型宿主防御蛋白 SPLUNC1 在严重哮喘中的作用短腭、肺和鼻上皮克隆 1 (SPLUNC1) 是一种来自大气道（鼻、气管和支气管）上皮的分泌蛋白。通过与 SARP 研究人员合作，我们发现 SPLUNC1 是细胞中减少最显着的蛋白质之一。我们发现，SPLUNC1 具有针对与哮喘恶化有关的人类鼻病毒和细菌的宿主防御功能，而哮喘恶化是哮喘发病率、死亡率和医疗费用的主要原因。过敏原挑战后的过敏性炎症（例如，与哮喘恶化相关的嗜酸性粒细胞和粘液）此外，人类转基因过度表达。小鼠气道中的 SPLUNC1 可减轻过敏原诱导的嗜酸性粒细胞炎症，然而，SPLUNC1 在人类严重哮喘中的作用尚不清楚。与 SARP 及其数据协调中心合作，我们将定义 SPLUNC1 在严重哮喘表型中的作用此外，我们将与 4 个 SARP 站点合作收集刷检活体。我们在哮喘发作期间对哮喘儿童和成人的鼻气道上皮细胞进行分析，以确定较低的基线 SPLUNC1 水平是否会使患者容易受到鼻病毒感染和哮喘发作。最后，我们将从机制上确定 SPLUNC1 的抗病毒和抗炎功能，这对于预防至关重要。成功完成这一时间敏感的辅助 R01 提案将指导使用 SPLUNC1 作为生物标志物和预防或治疗的新疗法。治疗哮喘急性发作。