Implications and Stability of Clinical and Molecular Phenotypes of Severe Asthma

描述（由申请人提供）：SARP 1 / 2确认了重度哮喘与轻度哮喘的临床/病理差异，并在基线时确定了不同的重度哮喘表型。观察到其他病理异常发生在群集内和跨群集，这些群集与症状、加重倾向和治疗反应的相似性有关。然而，关于这些临床或病理表型的稳定性，没有什么是了解的。发表的SARP II数据显示，在严重哮喘患者中，乳糜酶阳性肥大细胞（MCTC）在粘膜下层和上皮中占主导地位，有证据表明其激活状态发生了改变。初步数据表明，管腔MCTC mRNA的特征和激活模式甚至可以更好地区分有症状和易加重的重度哮喘和轻度哮喘。在3个主要的严重哮喘群中至少有2个存在这种MC特征。然而，这些变化背后的机制，这些MCs与上皮/炎症细胞的相互作用及其长期影响（和稳定性）尚不清楚。本应用程序的目标是建立一个纵向方案，能够识别哮喘表型及其对哮喘和严重哮喘的成人和儿童的长期影响，并评估其稳定性。该纵向协议将与确定MCTC分子表型的机制研究交叉，将其与遗传特征以及短期/长期细胞，临床，生理和放射学结果联系起来，然后分析其随时间的稳定性。最后，该提案将机械地确定这种肥大细胞特征对人气道上皮细胞的影响。这种体外/体内机制和纵向分子和临床表型的创新组合极有可能发现严重哮喘的新分子靶点。

DESCRIPTION (provided by applicant): SARP l/ll recognized clinical/pathologic differences of severe asthma compared to milder asthma and identified distinct severe asthma phentoypes at baseline. Additional pathobiologic abnormalities were observed to occur in and across clusters which linked similarities in symptoms, exacerbation predilection, treatment response. Yet, nothing is understood regarding the stability of implications of these clinical or pathologic phenotypes. Published SARP II data show that chymase positive mast cells (MCTC) predominate in the submucosa and epithelium in severe asthma, with evidence for an altered activation status. Preliminary data suggest that a luminal MCTC mRNA signature and activation pattern even better differentiates symptomatic and exacerbation prone severe from milder asthma. This MC signature is present across at least 2 of the 3 predominant severe asthma clusters. However, the mechanisms behind these changes, the interaction of these MCs with epithelial/inflammatory cells and their long term effects (and stability) are poorly understood. The goals of this application are to establish a longitudinal protocol capable of identifying asthma phenotypes and their long term implications in both adults and children with asthma and severe asthma, as well as evaluating their stability. This longitudinal protocol will intersect with mechanistic studies which identify a MCTC molecular phenotype, relate it to genetic characteristics as well as short/long term cellular, clinical, physiologic and radiologic outcomes and then analyze its stability over time. Finally, the proposal will mechanistically determine the impact of this mast cell signature on human airway epithelial cells. This innovative combination of in vitro/in vivo mechanistic and longitudinal molecular and clinical phenotyping is highly likely to uncover new molecular targets for severe asthma. RELEVANCE (See instructions): Severe asthma, impacts a minority of asthmatics, but accounts for a majority of the costs. While treatment of asthma has improved, severe asthma remains problematic and poorly treated. The proposed studies will identify new/novel molecular pathways, link them to baseline and longitudinal clinical, physiologic and radiologic outcomes and assess their stability over time leading to new molecular targets for therapy.