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

基本信息

批准号：
8316377
负责人：
Sally E Wenzel
金额：
$ 68.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-09 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316377
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 clinical phenotype cost genome wide association study improved in vivo innovation mast cell molecular phenotype novel response treatment response

项目摘要

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）：与温和的哮喘相比，SARP L/LL认识到严重哮喘的临床/病理差异，并在基线时鉴定出明显的严重哮喘疾病。观察到其他病理生物学异常发生在群体中和跨簇中，这与症状相似，加剧偏见，治疗反应联系在一起。然而，关于这些临床或病理表型的影响的稳定性，没有什么理解的。已发表的SARP II数据表明，在严重哮喘中，Chymase阳性肥大细胞（MCTC）占主层和上皮的占主导地位，并且有证据表明活化状态改变。初步数据表明，Luminal MCTC mRNA特征和激活模式甚至可以更好地区分有症状和恶化的严重性与温和哮喘。在3个主要的严重哮喘簇中，至少有2个MC签名存在。然而，这些变化背后的机制，这些MC与上皮/炎症细胞的相互作用及其长期效应（以及稳定性）的相互作用很少。该应用的目标是建立能够鉴定哮喘表型及其在哮喘和严重哮喘儿童中的长期影响的纵向方案，并评估其稳定性。该纵向方案将与鉴定MCTC分子表型的机理研究相交，将其与遗传特征以及短/长期细胞，临床，生理和放射学结果相关联，然后随时间分析其稳定性。最后，该提案将机械地确定该肥大细胞特征对人气道上皮细胞的影响。体外/体内机械和纵向分子和临床表型的这种创新组合很可能会发现严重哮喘的新分子靶标。相关性（请参阅说明）：严重的哮喘，会影响少数哮喘患者，但占大部分费用。虽然哮喘的治疗有所改善，但严重的哮喘仍然有问题且治疗不佳。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，生理和放射学结局联系起来，并随着时间的推移评估它们的稳定性，从而导致新的分子治疗靶标。