METALLOELASTASE INDUCTION FOLLOWING INTEGRIN KNOCKOUT

描述 （根据申请人？大卫莫里斯医生是一位肺科医生， 重症监护医生，坚定地致力于学术事业， 呼吸细胞和分子生物学独立研究员。他 特别感兴趣的是肺重塑。通过在肺生物学方面的工作 他在UCSF/SFGH中心发现了一种新的支气管炎动物模型， 由上皮整合素（α 2- beta6）。他提出了一项高级研究培训计划， 由整合素生物学专家指导的独立实验研究 (Dr. Dean Sheppard）;包括矩阵专家在内的研究咨询委员会 金属蛋白酶（Zena Werb博士），蛋白酶生物学（Caughey博士），以及 肺免疫学（Erle博士）;和正式的教学计划，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，整合素α 2-β 6的表面上的 呼吸道上皮细胞调节肺泡巨噬细胞表达 巨噬细胞金属弹性蛋白酶（MME，MMP-12），从而调节气道 炎症和基质降解。他将通过以下方式阐述这一假设： 三个具体目标。首先，他将确定β 6的哪些区域 整合素亚单位对防止持续性MMP-12（MME）至关重要 肺泡巨噬细胞过度表达，避免肺气肿的发展 在β 6-/-小鼠中使用新的转基因品系。其次，他将确定 MMP-12（MME）上调在募集和激活 巨噬细胞和淋巴细胞。 最后，他将确定转化生长因子β 1的作用， α 2-β 6介导的潜在TGF β 1活化在调节 气道炎症和MMP-12（MME）表达在体内使用两种腺病毒载体 基因转移和转基因方法。这项工作有望产生 对慢性气道疾病和慢性呼吸道疾病的基础生物学的重要见解， 炎症和肺气肿。Morris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， 培训独立学术肺科学家的杰出记录。的 医学系和LBC完全致力于莫里斯博士？职业生涯 发展，并提供一切必要资源， 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.