Evolving Microenvironments in Airway Inflammation

描述(申请人提供)：本申请申请资金，以继续补充，多学科的慢性炎症的呼吸道和肺重塑机制的研究。考伊、麦克唐纳、巴鲁克和克鲁梅尔博士密切合作，揭示了免疫细胞、肽酶和生长因子在重塑的病理生理学中所扮演的重要角色。这些研究的洞察力，包括淋巴管、肥大细胞、淋巴细胞和树突状细胞曾经不为人知的作用，为理解炎症的AIN/VaV黏膜微环境结构变化的演变提供了新的范式，并对慢性病的病因和治疗具有重要意义。接下来，该团队将使用生化、细胞和生理方法，包括实时双光子成像，来定义重塑的触发因素、后果和可逆性，并强调控制分辨率的因素。由考伊博士领导的项目1将使用药物酶和遗传工具来探索气道肽酶在重塑和宿主防御中的作用，重点是肥大细胞和上皮跨膜肽酶在消解炎症和防御支原体方面的作用。由克鲁梅尔博士领导的项目2将使用报告小鼠的新型双光子实时成像来确定T细胞、抗原呈递细胞、肥大细胞和淋巴管之间随着炎症微环境的演变和重塑而相互作用的位置、性质和重要性。由麦克唐纳博士领导的项目3将使用条件突变小鼠和新型抑制剂来确定淋巴管生成和血管生成在持续呼吸道炎症中的细胞机制、后果和可逆性。在这里，重点将强调推动淋巴管和血管增殖和重塑的因素的细胞作用，并利用淋巴和血管重塑在机械、时间和功能上是不同的发现。每个项目都受益于克鲁梅尔博士和巴鲁克博士领导的促进支原体感染、小鼠基因分型和活细胞成像的科学核心。这些计划将确保该计划关于呼吸道炎症和重塑的分子和细胞机制的合作研究的传统将继续产生具有基本和翻译重要性的见解。(摘要结束)

DESCRIPTION (provided by applicant): This application requests funding to continue complementary, multidisciplinary studies of mechanisms of airway and lung remodeling in chronic inflammation. Drs. Caughey, McDonald, Baluk and Krummel collaborated closely to reveal important roles played by immune cells, peptidases, and growth factors in the pathophysiology of remodeling. Insights from the studies, including once unsuspected roles for lymphatic vessels, mast cells, lymphocytes and dendritic cells, suggest new paradigms for understanding evolution of structural changes in mucosal microenvironments in inflamed ain/vays, with implications for causes and treatment of chronic disease. Going fooA^ard, the team will use biochemical, cellular and physiological approaches, including real time two-photon imaging, to define the triggers, consequences and reversibility of remodeling, emphasizing factors governing resolution. Project 1, led by Dr. Caughey, will use pharmacoenzymatic and genetic tools to explore roles of airway peptidases in remodeling and host defense, focusing on mast cell and epithelial transmembrane peptidase contributions to resolution of inflammation and defense against mycoplasma. Project 2, led by Dr Krummel, will use novel two-photon live imaging of reporter mice to identify sites, nature and importance of interactions between T-cells, antigen-presenting cells, mast cells and lymphatics as ainway microenvironments evolve and remodel in inflammation. Project 3, led by Dr. McDonald, will use conditional mutant mice and novel inhibitors to determine cellular mechanisms, consequences and reversibility of lymphangiogenesis and angiogenesis in sustained airway inflammation. Here, emphasis will be on cellular actions of factors that drive proliferation and remodeling of lymphatics and blood vessels, and exploitation of findings that lymphatic and blood vessel remodeling are mechanistically, temporally and functionally distinct. Each of the projects benefits from a scientific core led by Drs. Krummel and Baluk to facilitate mycoplasmal infection, mouse genotyping, and live cell imaging. These plans will ensure that the Program's tradition of collaborative research on molecular and cellular mechanisms of airway inflammation and remodeling will continue to yield insights of basic and translational importance. (End of Abstract)