Implications and Stability of Clinical and Molecular Phenotypes of Severe Asthma

描述(申请人提供)：SAPP L/11承认与轻度哮喘相比，重度哮喘的临床/病理差异，并在基线时识别出不同的重度哮喘表型。观察到其他病理生物学异常发生在集群内和集群之间，这些异常与症状、加重倾向、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尚不清楚。已发表的SARP II数据显示，重度哮喘患者的粘膜下层和上皮中以糜酶阳性的肥大细胞(MCTC)为主，有证据表明激活状态发生了变化。初步数据表明，管腔MCTC mRNA的签名和激活模式甚至可以更好地区分症状和加重倾向的严重哮喘和轻度哮喘。这种MC特征至少存在于3个主要的严重哮喘集群中的2个。然而，这些变化背后的机制、这些MC与上皮细胞/炎症细胞的相互作用以及它们的长期影响(和稳定性)还知之甚少。这项应用的目标是建立一种纵向方案，能够识别哮喘表型及其在成人和儿童哮喘和严重哮喘中的长期影响，并评估其稳定性。这一纵向方案将与机制研究交叉，这些研究确定MCTC分子表型，将其与遗传特征以及短期/长期细胞、临床、生理学和放射学结果联系起来，然后分析其随时间的稳定性。最后，该提案将从机械上确定肥大细胞签名对人类呼吸道上皮细胞的影响。这种体外/体内机制以及纵向分子和临床表型的创新组合极有可能发现治疗严重哮喘的新的分子靶点。 相关性(见说明)：严重哮喘影响少数哮喘患者，但占成本的大部分。虽然哮喘的治疗有所改善，但严重哮喘仍然存在问题，治疗效果不佳。拟议的研究将确定新的/新的分子途径，将它们与基线和纵向的临床、生理和放射结果联系起来，并评估它们随着时间的推移的稳定性，从而为治疗提供新的分子靶点。

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.