METALLOELASTASE INDUCTION FOLLOWING INTEGRIN KNOCKOUT

描述 (改编自申请者S摘要)莫里斯医生是一名肺部疾病 重症监护医生，对学术生涯有强烈的承诺 呼吸系统细胞和分子生物学方面的独立研究员。他的 尤其令人感兴趣的是肺重塑。通过肺生物学方面的工作 在加州大学旧金山分校的中心，他发现了一种新的支气管炎动物模型和 上皮整合素(α2-)失活所致的肺气肿 Beta6)。他提出了一项高级研究培训计划，其中包括 由整合素生物学专家指导的独立实验研究 (迪恩·谢泼德博士)；包括矩阵专家在内的研究咨询委员会 金属蛋白酶(泽纳·韦伯博士)、蛋白酶生物学(考希博士)，以及 肺部免疫学(Erle博士)；以及正式的教学计划，包括 生物化学、细胞生物学和免疫学课程。他的研究计划 将解决的假设是整合素α2-β6在细胞表面 呼吸道上皮细胞对肺泡巨噬细胞表达的调节 巨噬细胞金属弹性酶(Mme，MMP12)调节呼吸道功能的研究 炎症和基质降解。他将通过以下方式阐述这一假说 三个具体目标。首先，他将确定Beta6的哪些区域 整合素亚基是防止持续基质金属蛋白酶-12(MME)的关键 肺泡巨噬细胞过度表达与防止肺气肿的发生 在使用新转基因品系的Beta6/-小鼠中。第二，他将决定 基质金属蛋白酶-12(MME)上调在血管内皮细胞募集和激活中的作用 利用双基因敲除小鼠的Beta6-/-小鼠的巨噬细胞和淋巴细胞。 最后，他将确定转化生长因子Beta1的作用，以及 α2-β6介导的潜伏性转化生长因子β1的激活在调节血管生成中的作用 两种腺载体体内气道炎症与基质金属蛋白酶-12(MME)的表达 基因转移和转基因方法。这项工作有望取得成果。 对两种慢性呼吸道基础生物学的重要见解 炎症和肺气肿。莫里斯医生将在肺部完成这项工作 生物中心(LBC)，国际公认的研究中心 培养独立的肺科学术科学家的杰出记录。这个 医学部和LBC都全力支持莫里斯医生吗？职业生涯 发展和提供一切必要的资源，以促进 圆满完成这项工作。

DESCRIPTION (Adapted from applicant?s abstract) Dr. David Morris is a pulmonary and critical care physician with a strong commitment to an academic career as an independent investigator in respiratory cellular and molecular biology. His particular interest is lung remodeling. Through work in the Lung Biology Center at UCSF/SFGH he has identified a novel animal model of bronchitis and emphysema resulting from inactivation of an epithelial integrin (alpha2- beta6). He is proposing a program of advanced research training consisting of independent experimental studies mentored by an expert in integrin biology (Dr. Dean Sheppard); a research advisory committee including experts on matrix metalloproteinases (Dr. Zena Werb), protease biology (Dr. Caughey), and pulmonary immunology (Dr. Erle); and a formal didactic program including courses in biochemistry, cell biology, and immunology. His research program will address the hypothesis that the integrin alpha2-beta6 on the surface of respiratory epithelial cells modulates alveolar macrophage expression of Macrophage Metalloelastase (MME, MMP-12) thereby regulating airway inflammation, and matrix degradation. He will address this hypothesis through three specific aims. First, he will determine which regions of the beta6 integrin subunit are critical to prevent persistent MMP-12 (MME) overexpression by alveolar macrophages and avert the development of emphysema in beta6 -/- mice using novel transgenic lines. Second, he will determine the role of MMP-12 (MME) upregulation in the recruitment and activation of macrophages and lymphocytes in beta6 -/- mice using double knockout mice. Finally, he will determine the role of Transforming Growth Factor Beta1, and of alpha2-beta6 mediated activation of latent TGFbeta1 in the regulation of airway inflammation and MMP-12 (MME) expression in vivo using both adenovector gene transfer and transgenic approaches. This work promises to yield important insights into the fundamental biology underlying both chronic airway inflammation and emphysema. Dr. Morris will complete this work in the Lung Biology Center (LBC), internationally recognized research center with an outstanding record of training independent academic pulmonary scientists. The Department of Medicine and LBC are fully committed to Dr. Morris? career development and to making all necessary resources available to facilitate successful completion of this work.