LINKING OPTICS AND MECHANICS IN AIRWAY MODELS OF FIBROSIS

连接纤维化气道模型中的光学和力学

• 批准号: 8169522
• 负责人: Steven CARL George
• 金额: $ 0.21万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169522
• 关键词: Acute; Address; Asthma; Biological; Biological Assay; Breathing; Chemicals; Chronic; Collagen; Computer Retrieval of Information on Scientific Projects Database; Connective Tissue; Cornea; Development; Diagnostic; Diffuse; Disease; Embryonic Development; Epithelial; Epithelium; Fibrosis; Funding; Gel; Grant; Growth; Human; In Vitro; Infection; Inflammatory; Injury; Institution; Interleukin-13; Intubation; Lamina Propria; Laser Scanning Microscopy; Link; Mechanics; Mediator of activation protein; Microscopic; Modeling; Molecular; Mucous Membrane; Obstruction; Optical Coherence Tomography; Optics; Oryctolagus cuniculus; Population; Property; Research; Research Personnel; Resources; Respiratory physiology; Role; Severity of illness; Signal Pathway; Skin; Source; Stress; Structure; Structure of parenchyma of lung; Symptoms; Techniques; Tissue Engineering; Tissue Model; Tissues; Transforming Growth Factors; United States; United States National Institutes of Health; Wound Healing; airway remodeling; bronchial epithelium; in vivo Model; insight; minimally invasive; novel; protein expression; response; wound

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Airway epithelial injury occurs following inhalation of toxic agents, infection, intubation, and in a chronic repetitive disease such as asthma which impacts approximately 10% of the population in the United States. The wound repair response of the epithelium can induce changes in the structure and mechanical properties of the underlying connective tissue that can alter normal lung function. In bronchial asthma, alterations in the airway mucosa become more prominent as the disease progresses, and are correlated with disease severity, symptoms, and lung function (i.e., fixed airflow obstruction). The bronchial epithelium is known to modulate the development of the lung parenchyma during embryogenesis and these signaling pathways are likely "re-awakened" during chronic inflammatory diseases such as asthma resulting in pathological tissue growth. Our central hypothesis is that the wounded and inflamed epithelium secretes soluble mediators which diffuse into the underlying stroma at biologically active concentrations to significantly influence the mechanical properties of the matrix. Our specific aims are structured to specifically address the role of the epithelium in modulating the mechanical and optical properties of the subepithelial matrix: 1) utilizing both physical (compressive and scrape) and chemical (IL-13) injuries to the normal human bronchial epithelium in vitro, characterize the resulting impact on the optical and mechanical properties of the subepithelial matrix; 2) characterize the relationship between optical endpoints and the mechanical properties of both acellular and cellularized collagen gels in which collagen content, microstructure, and transforming growth factor-b2 are systematically altered; 3) quantify changes in the optical and mechanical properties of the tracheal mucosa in a rabbit model of repeated airway epithelial injury. The proposal combines novel tissue engineering techniques which mimic the anatomical arrangement of the epithelium and lamina propria, conventional biological techniques to assess protein expression, non-traditional minimally-invasive optical techniques (multiphoton laser scanning microscopy and optical coherence tomography) to assess bulk and microscopic changes in the matrix, and an in vivo model of tracheal epithelial injury. Completion of these aims will provide insight into the underlying mechanisms of airway remodeling, and provide a platform for non-invasive diagnostics for not only the airway, but other epithelial tissues subject to chronic or acute injury (e.g., cornea, skin). Three aims are addressed in this project: 1) Integrate validated molecular assays of collagen expression with new non-invasive optical techniques, 2) characterize the response of the in vitro tissue model to a physical denudation wound to the epithelium, and 3) characterize the response of the in vitro tissue model to a compressive stress wound to the epithelium.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 气道上皮损伤发生在吸入有毒物质、感染、插管后，以及慢性重复性疾病（例如影响美国约 10% 人口的哮喘）中。上皮的伤口修复反应可以引起下面结缔组织的结构和机械特性的变化，从而改变正常的肺功能。在支气管哮喘中，随着疾病的进展，气道粘膜的变化变得更加突出，并且与疾病的严重程度、症状和肺功能（即固定气流阻塞）相关。 众所周知，支气管上皮在胚胎发生过程中调节肺实质的发育，并且这些信号传导途径可能在慢性炎症性疾病（例如哮喘）期间“重新唤醒”，导致病理组织生长。 我们的中心假设是，受伤和发炎的上皮分泌可溶性介质，这些介质以生物活性浓度扩散到下面的基质中，从而显着影响基质的机械性能。 我们的具体目标旨在专门解决上皮在调节上皮下基质的机械和光学特性中的作用：1）利用对正常人支气管上皮的物理（压缩和刮擦）和化学（IL-13）损伤体外，表征对上皮下基质的光学和机械性能的影响； 2) 表征非细胞和细胞化胶原凝胶的光学终点与机械性能之间的关系，其中胶原含量、微观结构和转化生长因子-b2 被系统地改变； 3）量化反复气道上皮损伤的兔模型中气管粘膜的光学和机械特性的变化。该提案结合了模仿上皮和固有层解剖结构的新型组织工程技术、评估蛋白质表达的传统生物技术、评估体积和微观的非传统微创光学技术（多光子激光扫描显微镜和光学相干断层扫描）基质的变化以及气管上皮损伤的体内模型。完成这些目标将深入了解气道重塑的潜在机制，并为气道和其他遭受慢性或急性损伤的上皮组织（例如角膜、皮肤）的非侵入性诊断提供平台。 该项目实现了三个目标：1) 将经过验证的胶原蛋白表达分子测定与新的非侵入性光学技术相结合，2) 表征体外组织模型对上皮物理剥脱伤口的反应，3) 表征体外组织模型对上皮压应力伤口的反应。