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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：
9385687
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385687
关键词：
Adherence Adhesions Affect Anti-Inflammatory Agents Anti-inflammatory 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 Disease Environment Enzymes Epithelial Epithelial Cells Epithelium 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 Recruitment Activity Regulation Research Research Personnel Resources Respiratory physiology Role Scientist Signal Transduction Specimen Techniques Testing Training Transforming Growth Factor beta United States National Institutes of Health Universities Washington Work Wound Healing 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 permissiveness professor symposium translational approach versican

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.

项目摘要/摘要