Mechanisms of Remodeling in Chronic Airway Inflammation

描述（由申请人提供）： 该申请要求资助继续进行慢性炎症气道重塑机制的多学科研究。 Basbaum博士、Caughey博士、基林博士和McDonald博士多年来一直密切合作，并将继续努力了解气道重塑的细胞和分子病理生理学。 他们将集中在上皮细胞和炎症细胞，血管，炎症和蛋白酶的变化如何有助于气道重塑。 使用最先进的分子，细胞，形态学，免疫学和遗传学方法，多学科团队将从四个方面解决这个问题。 Basbaum博士领导的项目1将探索表面上皮病理性向下生长形成粘膜下腺体的机制，重点关注淋巴细胞和金属蛋白酶诱导剂EMMPRIN在腺体芽形成中的作用。 由Caughey博士领导的项目2将研究气道上皮细胞，肥大细胞和炎症细胞的细胞外蛋白酶在气道微血管和上皮重塑中的作用，强调蛋白酶分子行为和靶点的体外探索以及选定蛋白酶及其靶点在基因工程小鼠中的体内研究。 由基林博士领导的项目3将研究T和B淋巴细胞在触发抗体介导的气道微血管和上皮重塑中的分子机制，并将确定所涉及的介质。 McDonald博士的项目4将研究血管生成和淋巴管生成的机制、后果和可逆性，以探索微血管系统在维持慢性气道炎症中的守门功能以及淋巴生长缺陷在粘膜水肿中的作用。 新的转基因小鼠模型和肺支原体感染引起的慢性气道炎症小鼠将用于许多研究。 为了促进这些研究，每个项目都将得到由基林博士领导的小鼠基因分型和感染核心的支持。 该项目团队有着长期的合作研究传统，并使用多学科策略来研究气道炎症和重塑。 总的来说，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库将与创新的生物化学、体内模型系统一起使用，以解决慢性疾病中气道重塑的奥秘。 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，囊性纤维化和其他慢性炎症性气道疾病的典型气道壁的长期持续变化，影响越来越多的人口。

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.