Evolving Microenvironments in Airway Inflammation

描述（由申请人提供）：本申请申请资金用于继续对慢性炎症中气道和肺重塑机制进行补充的多学科研究。Drs。Caughey、McDonald、Baluk和Krummel密切合作，揭示了免疫细胞、肽酶和生长因子在重塑病理生理学中的重要作用。这些研究的见解，包括淋巴管、肥大细胞、淋巴细胞和树突状细胞曾经未被怀疑的作用，为理解炎症血管/血管粘膜微环境结构变化的演变提供了新的范式，对慢性疾病的病因和治疗具有重要意义。接下来，该团队将使用生化、细胞和生理学方法，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，强调控制分辨率的因素。项目1，由Caughey博士领导，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，重点关注肥大细胞和上皮跨膜肽酶在解决炎症和防御支原体中的作用。由Krummel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识别t细胞、抗原呈递细胞、肥大细胞和淋巴细胞之间相互作用的位置、性质和重要性，因为炎症中的微环境在进化和重塑。由McDonald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持续气道炎症中淋巴管生成和血管生成的细胞机制、后果和可逆性。在这里，重点将放在驱动淋巴和血管增殖和重塑的因素的细胞作用上，并利用淋巴和血管重塑在机制、时间和功能上的不同发现。每个项目都受益于一个由博士领导的科学核心。Krummel和Baluk促进支原体感染，小鼠基因分型和活细胞成像。这些计划将确保该项目在气道炎症和重塑的分子和细胞机制方面的合作研究传统将继续产生基础和转化重要性的见解。（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)