SPLUNC1 in Severe Asthma

 描述（由申请人提供）：严重哮喘折磨约10%的哮喘患者，但占用30 - 50%的哮喘相关医疗费用。必须了解严重哮喘特别是急性发作的发生机制。为了提高对严重哮喘的理解并开发更好的治疗方法，在过去的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成人和儿童严重哮喘研究，目前在美国的七个主要哮喘研究中心进行。目前的SARP（SARP 3）已开始收集上呼吸道和下呼吸道样本，以研究严重哮喘的病理生物学。这为我们进一步了解哮喘的自然史、疾病进展和新的治疗干预提供了前所未有的机会。然而，SARP 3方案不包括收集最小侵入性鼻气道上皮细胞，这是一种可以纵向重复以研究哮喘发病机制的方法。因此，我们提出了一个时间敏感的研究，通过使用鼻气道上皮细胞，以确定一种新的宿主防御蛋白SPLUNC 1在严重哮喘中的作用。短腭、肺和鼻上皮克隆1（SPLUNC 1）是来自大气道（鼻、气管和支气管）上皮细胞的分泌蛋白，并且在健康个体的上皮衬里液中丰富。通过与SARP研究人员的合作，我们确定SPLUNC 1是严重哮喘患者支气管肺泡灌洗液样本中最显著降低的蛋白质之一。我们发现SPLUNC 1发挥宿主防御功能，对抗与哮喘急性发作有关的人类鼻病毒和细菌-哮喘发病率，死亡率和医疗保健费用的主要原因。我们发现SPLUNC 1缺陷小鼠在过敏原攻击后具有夸大的气道过敏性炎症（例如，嗜酸性粒细胞和粘液，与哮喘恶化相关）。此外，小鼠气道中人SPLUNC 1的转基因过表达减弱了变应原诱导的嗜酸性粒细胞炎症。然而，SPLUNC 1在人类严重哮喘中的作用尚不清楚。我们推测，在哮喘气道中SPLUNC 1的下调增加了鼻病毒感染和相关的哮喘加重，从而导致哮喘严重程度。在与SARP及其数据协调中心的持续合作中，我们将确定SPLUNC 1在严重哮喘表型中的作用。此外，我们将与4个SARP研究中心合作，在哮喘急性发作期间从哮喘儿童和成人中收集刷取的活鼻气道上皮细胞，以确定较低的基线SPLUNC 1水平是否使患者易患鼻病毒感染和哮喘急性发作。最后，我们将从机制上确定SPLUNC 1的抗病毒和抗炎功能，这对预防哮喘急性发作至关重要。 成功完成这一具有时间敏感性的辅助R 01提案将指导SPLUNC 1作为生物标志物和预防或治疗急性哮喘加重的新疗法的使用。

 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.