METALLOELASTASE INDUCTION FOLLOWING INTEGRIN KNOCKOUT

整合素敲除后的金属弹性蛋白酶诱导

• 批准号: 6224361
• 负责人: David G Morris
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-08 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6224361
• 关键词: Adenoviridae; alveolar macrophages; cell growth regulation; cellular pathology; elastases; emphysema; enzyme activity; enzyme induction /repression; enzyme structure; gene expression; gene targeting; genetically modified animals; immunocytochemistry; inflammation; integrins; laboratory mouse; leukocyte activation /transformation; lymphocyte; metalloendopeptidases; molecular pathology; protein degradation; pulmonary fibrosis /granuloma; respiratory epithelium; transfection /expression vector; transforming growth factors

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.

描述 （改编自申请人的摘要）大卫·莫里斯博士是一位肺和 重症监护医师，作为一名坚定致力于学术事业的医生 呼吸细胞和分子生物学的独立研究者。他的 特别感兴趣的是肺重塑。通过肺生物学的工作 他在 UCSF/SFGH 中心发现了一种新的支气管炎动物模型 上皮整合素（α2-）失活导致的肺气肿 测试版6）。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 （迪安·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（Zena Werb 博士）、蛋白酶生物学（Caughey 博士）和 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 将解决整合素α2-β6在表面的假设 呼吸道上皮细胞调节肺泡巨噬细胞的表达 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。他将通过以下方式解决这个假设 三个具体目标。首先，他将确定 beta6 的哪些区域 整合素亚基对于预防持久性 MMP-12 (MME) 至关重要 肺泡巨噬细胞过度表达并避免肺气肿的发展 使用新型转基因品系在 beta6 -/- 小鼠中进行实验。其次，他将确定 MMP-12 (MME) 上调在招募和激活中的作用 使用双敲除小鼠的 beta6 -/- 小鼠中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 介导的潜在 TGFβ1 激活在调节中的作用 使用两种腺载体进行体内气道炎症和 MMP-12 (MME) 表达 基因转移和转基因方法。这项工作有望产生 对慢性气道基础生物学的重要见解 炎症和肺气肿。莫里斯博士将在肺部完成这项工作 生物中心 (LBC)，国际公认的研究中心，拥有 培养独立学术肺科科学家的杰出记录。这 医学系和 LBC 完全致力于莫里斯博士？职业 的发展并提供一切必要的资源以促进 顺利完成这项工作。