Implications and Stability of Clinical and Molecular Phenotypes of Severe Asthma

严重哮喘临床和分子表型的意义和稳定性

• 批准号: 9058585
• 负责人: Sally E Wenzel
• 金额: $ 66.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-09 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058585
• 关键词: Accounting; Adult; Asthma; Biological Markers; Bronchoalveolar Lavage; Cell physiology; Cells; Characteristics; Child; Childhood; Chymase; Clinical; Data; Epithelial; Epithelial Cells; Epithelium; Evaluation; Genetic; Genomics; Goals; Heterogeneity; Human; In Vitro; Inflammatory; Instruction; Link; Liquid substance; Long-Term Effects; Longitudinal Studies; Lung; Lymphocyte; Measurement; Measures; Messenger RNA; Minority; Molecular; Molecular Abnormality; Molecular Genetics; Molecular Profiling; Molecular Target; Outcome; Pathologic; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Plasma; Principal Investigator; Prostaglandin D2; Protocols documentation; Publishing; Respiratory physiology; Severities; Sputum; Submucosa; Symptoms; Time; Tryptase; asthmatic; clinical phenotype; cost; genome wide association study; improved; in vivo; innovation; mast cell; molecular phenotype; molecular targeted therapies; novel; response; treatment response

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.

描述（由申请人提供）：SARP l/ll 认识到严重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严重哮喘表型。观察到其他病理生物学异常发生在簇内和簇之间，这些异常与症状、恶化倾向、治疗反应的相似性有关。然而，对于这些临床或病理表型的影响的稳定性尚不清楚。已发表的 SARP II 数据显示，在严重哮喘患者的粘膜下层和上皮细胞中，糜烂酶阳性肥大细胞 (MCTC) 占主导地位，有证据表明激活状态发生了改变。初步数据表明，管腔 MCTC mRNA 特征和激活模式甚至可以更好地区分有症状和易恶化的重度哮喘和轻度哮喘。该 MC 特征存在于 3 个主要严重哮喘簇中的至少 2 个中。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及其长期影响（和稳定性）却知之甚少。该应用的目标是建立一个纵向方案，能够识别哮喘表型及其对患有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。该纵向方案将与识别 MCTC 分子表型的机制研究相交叉，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，该提案将从机械上确定这种肥大细胞特征对人类气道上皮细胞的影响。这种体外/体内机制和纵向分子及临床表型的创新组合极有可能发现严重哮喘的新分子靶标。 相关性（参见说明）：严重哮喘影响少数哮喘患者，但占大部分费用。虽然哮喘的治疗有所改善，但严重的哮喘仍然存在问题并且治疗效果不佳。拟议的研究将确定新的/新颖的分子途径，将它们与基线和纵向临床、生理和放射学结果联系起来，并评估它们随着时间的推移的稳定性，从而产生新的治疗分子靶点。