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 该应用程序是针对由患者的指导研究职业发展奖，标题为“ 严重哮喘的替代病理生物学。”我是医学助理教授 匹兹堡大学在台式鼠研究技术和生物信息学方面寻求额外的培训 和'OMICS分析是从台式过渡到转化性哮喘研究的过渡。我研究的重点是 关于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。 尽管在理解和处理传统描述的2型（T2）方面取得了长足的进步 新型生物学疗法哮喘的炎症，近50％的哮喘患者缺乏证据 途径，甚至有些注射T2的途径也无法对T2疗法做出很好的反应。更好地理解 哮喘中的其他炎症途径及其对疾病的贡献对于识别新颖的疾病至关重要 这些患者的治疗。我的初步数据证明了标记的T1炎症的存在 通过增加IFN-γ的表达，趋化因子CXCL10和CCL5以及T1表达组织居民 约30％的哮喘患者的记忆T细胞（T1 TRM）。这些患者往往患有更严重的哮喘，更大 加剧和更高的全身性皮质类固醇使用。但是，对样品的支气管镜检查的依赖 随着时间的流逝，我们研究该途径的临床效应的能力。此外，我们对 T1炎症对哮喘气道的影响以及T1 TRM细胞在维持/驱动这一方面的作用 表型未知。这项研究旨在提高我们对三种哮喘T1注入的理解 方法：（1）利用我们的T1主要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Maraviroc（CCR5抑制剂）在影响T1的特定更改中的重要性 气道上皮和肥大细胞患病率。 （3）多中心严重的哮喘研究计划提供 大量具有配对痰样品的哮喘受试者中的临床数据，这将使我们能够测量T1 炎症标记，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 识别T1高哮喘患者以备将来的试验。该项目将为小说提供独特的见解 在哮喘中理解的齿途径，有可能产生令人兴奋的新治疗选择 和严重疾病。这项研究还将为我提供获得生物信息学和技能的机会 大型“ OMICS数据集分析”将促进我作为重度翻译的物理科学家的发展 哮喘除了推进我的鼠模型技能。这项工作将在大学进行 匹兹堡在肺部，过敏和重症监护室的部门中具有良好的发展记录 物理科学家并拥有一个高度发展的基础设施，用于转化研究。我也有 组建了一个备受成就的多学科心态团队，该团队在哮喘中获得国际认可 研究，生物信息学和机器学习。