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Airway epithelial regulation of fibroblast hyaluronan and versican production in asthmatic airway inflammation

哮喘气道炎症中成纤维细胞透明质酸和多功能蛋白聚糖产生的气道上皮调节

基本信息

批准号：
10208933
负责人：
STEPHEN R REEVES
金额：
$ 16.23万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208933
关键词：
Adherence Adhesions Affect Airway Disease Anti-Inflammatory Agents Area Asthma Automobile Driving Autopsy Basic Science Binding Cells Cellular biology Child Childhood Childhood Asthma Clinical Clinical Research Coculture Techniques Data Data Analyses Deposition Development Dinoprostone Environment Enzymes Epithelial Epithelial Cells Equilibrium Extracellular Matrix Fibroblasts Funding Genes Germ Cells Goals Healthcare Human Hyaluronan In Vitro Inflammatory Investigation K-Series Research Career Programs Laboratories Lead Leukocytes Lung Maintenance Measures Mentors Mentorship Mesenchymal Methodology Modeling Molecular Weight Monoclonal Antibodies Pathogenesis Phenotype Play Process Production Property Proteomics Public Health Publications Pulmonology Regulation Research Research Personnel Resources Role Scientist Signal Transduction Specimen Structure Techniques Testing Training Transforming Growth Factor beta United States National Institutes of Health Universities Washington Work airborne allergen airway epithelium airway hyperresponsiveness airway inflammation airway obstruction airway remodeling asthmatic asthmatic airway base career career development cytokine eosinophil in vivo Model indexing innovation interest knock-down leukocyte activation mast cell migration monocyte neutrophil novel therapeutic intervention pediatric department professor pulmonary function recruit symposium translational approach versican wound healing

项目摘要

PROJECT SUMMARY / ABSTRACT This project is a NIH Mentored Clinical Scientist Research Career Development Award (K08) application for Dr. Stephen Reeves, an Acting Assistant Professor in the Department of Pediatrics at the University of Washington (UW). Dr. Reeves has completed his clinical training in Pediatric Pulmonary Medicine and has both a clinical and research interest in the treatment of pediatric asthma. Dr. Reeves’ specific research interest is understanding the role played by the airway epithelial cells (AECs) in regulating the production of extra- cellular matrix (ECM) by airway mesenchymal cells and alterations in this process that may predispose to airway inflammation. His long-term career goal is to establish himself as an independently-funded principle investigator studying these mechanisms in human cells using basic science and translational approaches. In order to achieve this goal, Dr. Reeves is requesting the NIH K08 support for additional training and mentorship in the following specific areas: (1) additional training in airway cell biology including cell-cell and cell-matrix interactions; (2) additional training in the methodology of ECM characterization and quantitation; (3) additional training in laboratory techniques related to gene knockdown and gene editing; (4) additional training in proteomic approaches and data analysis; (5) attendance of scientific conferences, career development seminars, and additional classroom-based training relevant to this project; and (6) mentorship in the development of an independent research focus with a goal of transitioning to scientific independence. In the present application, Dr. Reeves proposes studies to further investigate the role that AEC signaling plays in driving HA and VCAN deposition in the ECM by HLF. These studies will focus on following areas: Specific Aim 1) determining if primary asthmatic AECs drive HLFs to produce an ECM enriched in HA and VCAN as compared to AECs from healthy children; Specific Aim 2) determining if a HA- and VCAN-enriched ECM produced by HLFs conditioned by asthmatic AECs increases leukocyte adhesion, migration, and activation, as compared to ECM produced by HLFs co-cultured with healthy AECs; Specific Aim 3) determining if clinical indices of lung function and airway inflammation among AEC donors correlate with HA and VCAN accumulation in ECM, and with enhanced leukocyte adhesion, migration, and activation by ECM produced by co-cultured HLFs. These studies hold promise in furthering our understanding of how AECs may regulate ECM deposition by HLFs that ultimately protect against or predispose to inflammatory changes, which is at the present poorly understood. Furthermore, it is anticipated these studies would provide the publications and preliminary data needed to develop an independent research direction and apply for R01 funding at the end of the career development support.

项目概要/摘要该项目是 NIH 指导临床科学家研究职业发展奖 (K08) 博士的申请。史蒂芬·里夫斯 (Stephen Reeves)，美国大学儿科系代理助理教授华盛顿大学（UW）。 Reeves 博士已完成小儿肺科临床培训，并已对小儿哮喘治疗的临床和研究兴趣。 Reeves博士的具体研究兴趣正在了解气道上皮细胞（AEC）在调节额外的产生中所发挥的作用气道间充质细胞产生的细胞基质（ECM）以及该过程中的改变可能导致气道炎症。他的长期职业目标是成为一名独立资助的原则研究人员使用基础科学和转化方法研究人类细胞中的这些机制。为了实现这一目标，Reeves 博士请求 NIH K08 支持额外的培训和以下具体领域的指导：(1) 气道细胞生物学的额外培训，包括细胞间和细胞-基质相互作用； (2) ECM 表征和定量方法的额外培训； (3) 与基因敲低和基因编辑相关的实验室技术的额外培训； (4)额外培训蛋白质组学方法和数据分析； (5) 参加科学会议、职业发展研讨会以及与该项目相关的其他课堂培训； (6) 指导发展独立研究重点，目标是过渡到科学独立。在本申请中，Reeves 博士提出了进一步研究 AEC 信号传导所发挥的作用的研究通过 HLF 驱动 ECM 中的 HA 和 VCAN 沉积。这些研究将集中在以下领域：具体目标 1) 确定原发性哮喘 AEC 是否驱动 HLF 产生富含 HA 和 VCAN 的 ECM，如下所示与健康儿童的 AEC 相比；具体目标 2) 确定是否富含 HA 和 VCAN 的 ECM 由哮喘 AEC 调节的 HLF 产生，可增加白细胞粘附、迁移和激活，如与 HLF 与健康 AEC 共培养产生的 ECM 相比；具体目标 3) 确定临床是否 AEC 供体的肺功能和气道炎症指数与 HA 和 VCAN 相关 ECM 中的积累，并通过 ECM 产生的白细胞粘附、迁移和激活增强共培养 HLF。这些研究有望进一步加深我们对 AEC 如何调节 ECM 的理解 HLF 的沉积最终可以防止或诱发炎症变化，这是最重要的目前了解甚少。此外，预计这些研究将提供出版物和制定独立研究方向并在年底申请R01资助所需的初步数据职业发展支持。