Mechanisms of Remodeling in Chronic Airway Inflammation

描述(由申请人提供)： 这项申请要求提供资金，以继续对慢性炎症中呼吸道重塑机制的多学科研究。巴斯鲍姆博士、考伊博士、基林博士和麦克唐纳博士多年来一直在这个项目赠款项目中密切合作，并将继续努力了解呼吸道重塑的细胞和分子病理生理学。他们将专注于上皮细胞和炎症细胞、血管、淋巴管和蛋白酶的变化如何有助于呼吸道重建。使用最先进的分子、细胞、形态、免疫学和遗传学方法，多学科团队将通过四种方式解决这个问题。由Basbaum博士领导的项目1将探索表面上皮细胞病理性生长减慢形成粘膜下腺的机制，重点是淋巴细胞和金属蛋白酶诱导剂EMMPRIN在腺芽形成中的作用。项目2将研究来自呼吸道上皮细胞、肥大细胞和炎症细胞的胞外蛋白水解酶在呼吸道微血管和上皮细胞重建中的作用，重点是在体外探索蛋白水解酶的分子行为和靶点，以及在基因工程小鼠中对选定的蛋白水解酶及其靶点进行体内研究。由Killeen博士领导的项目3将研究T和B淋巴细胞在触发抗体介导的呼吸道微血管和上皮重塑中合作的分子机制，并将确定参与其中的介质。项目4，由McDonald博士发起，将研究血管生成和淋巴管生成的机制、后果和可逆性，以探索微血管在维持慢性呼吸道炎症中的把关功能，以及缺陷在淋巴管生长在粘膜水肿中的作用。新型转基因小鼠模型和肺支原体感染所致慢性呼吸道炎症小鼠将被用于许多研究。为了促进这些研究，每个项目都将得到由Killeen博士领导的小鼠基因分型和感染核心的支持。项目团队在合作研究和使用多学科策略研究呼吸道炎症和重塑方面有着悠久的传统。他们在细胞和分子生物学、酶学、显微成像和免疫学方面的强大经验和技能将与创新的生化体内模型系统一起用于解开慢性疾病中呼吸道重塑的谜团。了解重塑的原因将提出新的策略，以预防或逆转哮喘、支气管炎、囊性纤维化和其他影响越来越多人口的慢性炎症性呼吸道疾病典型的气道壁长期变化。

DESCRIPTION (provided by applicant): This application requests funding to continue multidisciplinary studies of mechanisms of airway remodeling in chronic inflammation. Drs. Basbaum, Caughey, Killeen, and McDonald have collaborated closely in this Program Project Grant for many years and will continue their efforts to understand the cellular and molecular pathophysiology of airway remodeling. They will focus on how changes in epithelial and inflammatory cells, blood vessels, lymphatics, and proteases contribute to airway remodeling. Using state-of-the-art molecular, cellular, morphological, immunological, and genetic approaches, the multidisciplinary team will approach the problem in four ways. Project 1, led by Dr. Basbaum, will explore mechanisms of pathological down-growth of surface epithelium to form submucosal glands, focusing on the roles of lymphocytes and the metalloproteinase inducer EMMPRIN in gland bud formation. Project 2, led by Dr. Caughey, will investigate roles of extracellular proteases from airway epithelial cells, mast cells, and inflammatory cells in remodeling of the airway microvasculature and epithelium, emphasizing in vitro explorations of the molecular behavior and targets of proteases and in vivo studies of selected proteases and their targets in genetically engineered mice. Project 3, led by Dr. Killeen, will examine molecular mechanisms whereby T and B lymphocytes cooperate in triggering antibody-mediated remodeling of the airway microvasculature and epithelium and will identify the mediators involved. Project 4, let by Dr. McDonald, will examine the mechanisms, consequences, and reversibility of angiogenesis and lymphangiogenesis to explore the gate-keeper function of the microvasculature in sustaining chronic airway inflammation and the role of defects in lymphatic growth in mucosal edema. Novel transgenic mouse models and mice with chronic airway inflammation from Mycoplasma pulmonis infection will be used in many investigations. To facilitate these studies, each of the projects will be supported by a Mouse Genotyping and Infection Core, led by Dr. Killeen. The Program Project team has a long tradition of collaborative research and use of multidisciplinary strategies for studying airway inflammation and remodeling. Collectively, their powerful armory of experience and skills in cellular and molecular biology, enzymology, microscopic imaging, and immunology will be used with innovative biochemical, in vivo model systems to solve the mysteries of airway remodeling in chronic disease. Understanding the causes of remodeling will suggest new strategies to prevent or reverse the long lasting changes in the airway wall typical of asthma, bronchitis, cystic fibrosis, and other chronic inflammatory airway diseases affecting a growing share of population.