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

• 批准号: 9975887
• 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
• 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/9975887
• 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; 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; Regulation; Research; Research Personnel; Resources; Respiratory physiology; 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; recruit; symposium; translational approach; versican; wound healing

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 该项目是美国国立卫生研究院指导临床科学家研究职业发展奖(K08)的博士申请。 斯蒂芬·里夫斯，加州大学儿科系代理助理教授 华盛顿(UW)。里夫斯医生已经完成了他的儿科肺部医学临床培训，并 对儿童哮喘的治疗具有临床和研究兴趣。里夫斯博士的特殊研究兴趣 正在了解呼吸道上皮细胞(AECs)在调节细胞外基质产生中所起的作用 气道间充质细胞的细胞基质(ECM)及在这一过程中可能易患 呼吸道发炎。他的长期职业目标是使自己成为一名自负盈亏的校长。 研究人员使用基础科学和翻译方法研究人类细胞中的这些机制。 为了实现这一目标，里夫斯博士正在请求NIH K08提供额外的培训和支持 在以下具体领域提供指导：(1)关于呼吸道细胞生物学的额外培训，包括细胞-细胞和 细胞-基质相互作用；(2)细胞外基质表征和定量方法方面的额外培训；(3) 与基因敲除和基因编辑有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)出席科学会议、职业发展 与该项目相关的研讨会和额外的课堂培训；以及(6)在 发展独立的研究重点，目标是向科学独立过渡。 在目前的应用中，里夫斯博士提出了进一步研究AEC信号所起作用的研究 HLF在ECM中驱动HA和VCaN的沉积。这些研究将集中在以下几个方面： 目的1)确定原发哮喘AEC是否驱动HLF产生富含HA和VCaN AS的ECM 与健康儿童的血管内皮细胞比较；特定目的2)确定HA和VCAN富含的ECM 由哮喘AECs调节产生的HLFS可增加白细胞的黏附、迁移和激活，如 与HLFS与健康AEC共培养产生的ECM进行比较；特异性目标3)确定是否临床 AEC供者肺功能和气道炎症指标与HA、VCAN的相关性 在细胞外基质中积聚，并通过产生的细胞外基质增强白细胞的黏附、迁移和激活 共培养的HLCs。这些研究有望加深我们对aecs如何调控ecm的理解。 HLF的沉积，最终防止或倾向于炎症变化，这是在 目前人们对此知之甚少。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末申请R01资金所需的初步数据 对职业发展的支持。