An Alternative Pathobiology underlying Severe Asthma

严重哮喘的替代病理学

• 批准号: 10736884
• 负责人: Marc Gauthier
• 金额: $ 16.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736884
• 关键词: Adrenal Cortex Hormones; Adult; Affect; Antigens; Asthma; Automobile Driving; Award; Bioinformatics; Biological; Biological Markers; Biological Products; Biological Response Modifier Therapy; Biopsy; Bronchoalveolar Lavage; Bronchoscopy; CCR5 gene; CXCL10 gene; CXCR3 gene; Cells; Clinical; Clinical Data; Critical Care; Data; Data Set; Development; Disease; Eosinophilia; Epithelial Cells; Epithelium; FDA approved; Fostering; Future; High Prevalence; Human; Hypersensitivity; Immune; Inflammation; Inflammatory; Infrastructure; Interferon Type II; Interferons; International; Link; Lung; Machine Learning; Maintenance; Measures; Mediating; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentorship; Mus; Natural History; Neutrophilia; Outcome; Participant; Pathologic; Pathway interactions; Patients; Persons; Phenotype; Physicians; Prevalence; Pulmonary Inflammation; Research; Research Technics; Resistance; Role; Sampling; Scientist; Severity of illness; Signal Transduction; Sputum; Steroids; Time; Tissues; Training; Translational Research; Universities; Work; airway epithelium; airway hyperresponsiveness; airway obstruction; asthma model; asthmatic; asthmatic patient; biomarker development; chemokine; clinical effect; cohort; cytokine; disorder control; improved; inflammatory marker; inhibitor; insight; mast cell; mouse model; multidisciplinary; novel; novel therapeutics; professor; programs; receptor; recruit; response; skill acquisition; skills; targeted treatment; tissue resident memory T cell; transcriptome sequencing; translational physician; treatment response

Project Abstract This application is for a Mentored Patient-Oriented Research Career Development Award entitled “An Alternative Pathobiology underlying Severe Asthma.” I am an Assistant Professor of Medicine at the University of Pittsburgh seeking additional training in benchtop murine research techniques and bioinformatics and ‘omics analysis to transition from benchtop to translational asthma research. The focus of my research is on the role of Type-1 (T1) inflammation in asthma and how this pathway may contribute to disease severity. While great strides have been made in understanding and treating traditionally described Type-2 (T2) inflammation in asthma with novel biologic therapies, nearly 50% of asthma patients lack evidence of this pathway, and even some with T2 inflammation fail to respond well to T2 therapies. A better understanding of other inflammatory pathways in asthma and how they contribute to disease is essential to identifying novel therapeutics for these patients. My preliminary data have demonstrated the presence of T1 inflammation marked by increased expression of IFN-γ, the chemokines CXCL10 and CCL5 as well as T1 expressing tissue resident memory T-cells (T1 TRM) in ~30% of asthma patients. These patients tend to have more severe asthma, greater exacerbations and higher use of systemic corticosteroids. However, the reliance on bronchoscopy for samples has limited our ability to study the clinical effects of this pathway over time. Furthermore, our understanding of the effects of T1 inflammation on the airways in asthma and the role of T1 TRM cells in maintaining/driving this phenotype are unknown. This study aims to improve our understanding of asthmatic T1 inflammation in three ways: (1) Utilize our T1 dominant murine severe asthma model to assess TRM establishment and reactivation in T1High asthma. (2) To assess the importance of maraviroc (a CCR5 inhibitor) in effecting T1 specific changes on the airway epithelium and mast cell prevalence. (3) The multicenter Severe Asthma Research Program provides clinical data in a large number of asthma subjects with paired sputum samples that will allow us to measure T1 inflammatory markers, assess their correlation with clinical outcomes and identify future biomarkers to better identify T1High asthmatics for future trials. This project will provide unique insight into a novel and poorly understood pathway in asthma with the potential to yield exciting new treatment options for a highly prevalent and severe disease. This study will also provide the opportunity for me to acquire skills in bioinformatics and large ‘omics dataset analysis that will foster my development as a translational physician scientist in severe asthma in addition to advancing my murine model skillset. The work will be carried out at the University of Pittsburgh in the division of Pulmonary, Allergy and Critical Care which has a strong track record of developing physician scientists and boasts a highly developed infrastructure for translational research. I have also assembled a highly accomplished multi-disciplinary mentorship team that is internationally recognized in asthma research, bioinformatics and machine learning.

项目摘要 本申请旨在申请一项以患者为导向的研究职业发展奖，题为“An 严重哮喘的替代病理学。” 匹兹堡大学寻求台式小鼠研究技术和生物信息学方面的额外培训 和“从台式哮喘研究过渡到转化性哮喘研究的组学分析”。 1 型 (T1) 炎症在哮喘中的作用以及该途径如何导致疾病严重程度。 虽然在理解和治疗传统描述的 2 型 (T2) 方面已经取得了巨大进步 使用新型生物疗法治疗哮喘炎症，但近 50% 的哮喘患者缺乏这方面的证据 途径，甚至一些患有 T2 炎症的人也无法对 T2 疗法产生良好的反应。 哮喘的其他炎症途径以及它们如何导致疾病对于识别新的炎症途径至关重要 我的初步数据表明这些患者存在 T1 标记炎症。 通过增加 IFN-γ、趋化因子 CXCL10 和 CCL5 以及 T1 表达组织驻留的表达 约 30% 的哮喘患者存在记忆 T 细胞 (T1 TRM) 这些患者往往患有更严重的哮喘。 病情加重和全身性皮质类固醇的使用较多，但样本依赖于支气管镜检查。 随着时间的推移，限制了我们研究该途径临床效果的能力。 T1 炎症对哮喘气道的影响以及 T1 TRM 细胞在维持/驱动这一过程中的作用 表型未知。本研究旨在提高我们对三种哮喘 T1 炎症的认识。 方法：（1）利用我们的T1显性小鼠严重哮喘模型来评估TRM的建立和重新激活 T1 高哮喘 (2) 评估马拉韦罗（一种 CCR5 抑制剂）对影响 T1 特异性变化的重要性。 (3) 多中心严重哮喘研究计划提供 大量哮喘受试者的临床数据以及配对痰样本，使我们能够测量 T1 炎症标志物，评估其与临床结果的相关性并确定未来的生物标志物以更好地 为未来的试验确定 T1High 哮喘患者。该项目将为一种新颖且不良的哮喘患者提供独特的见解。 已知的哮喘途径有可能为高度流行的哮喘病带来令人兴奋的新治疗选择 这项研究还将为我提供获得生物信息学和严重疾病方面的技能的机会。 大型组学数据集分析将促进我作为一名转化医学科学家的发展 除了提高我的小鼠模型技能外，这项工作还将在大学进行。 匹兹堡的肺科、过敏科和重症监护科在开发方面拥有良好的记录 我还拥有医学科学家，并拥有高度发达的转化研究基础设施。 组建了一支在哮喘领域得到国际认可的高水平多学科指导团队 研究、生物信息学和机器学习。