Defining the Role of MAGP-2 in Microfibril Assembly

定义 MAGP-2 在微纤维组装中的作用

• 批准号: 6538001
• 负责人: J MICHAEL SHIPLEY
• 金额: $ 26.16万
• 依托单位: BARNES-JEWISH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6538001
• 关键词: elastic tissue; extracellular matrix; extracellular matrix proteins; fibrillin; fibroblasts; gene targeting; glycoprotein structure; glycoproteins; growth /development; histogenesis; laboratory mouse; lung; molecular assembly /self assembly; protein binding; protein localization

DESCRIPTION (Applicant's Abstract): Microfibril-associated glycoprotein-2 (MAGP-2) is one of two MAGPs, both of which are integral components of microfibrils associated with elastic fibers. MAGP-2 is shown herein to bind specifically to fibrillin-1 and -2, two well-characterized constituents of extracellular microfibrils that are genetically linked to heritable disorders of elastic fibers known as the Marfan syndrome and congenital contractural arachnodactyly, respectively. MAGP-2 also binds MAGP- 1. In this proposal, the function of MAGP-2 within the microfibril will be examined. MAGP-2 binding sites on both fibrillin-1 and MAGP-1 will be localized, as will determinants within MAGP-2 responsible for these. The spatial and temporal pattern of MAGP-2 gene expression in the developing mouse will be determined, and coexpression/colocalization with other major elastic fiber components will be assessed. MAGP-2 expression in the MAGP-1 knockout mouse will also be investigated. A mouse harboring a targeted disruption of the MAGP-2 gene will be generated and assessed for developmental abnormalities. Microfibrils in MAGP-2 -/- mice will be studied at the ultrastructural level. If the mouse dies during embryonic development, primary fibroblast cultures will be derived from MAGP-2 -/- lungs and used to study the role of MAGP-2 in microfibril assembly in vitro. The role of MAGP-2 in lung branching morphogenesis will also be studied in knockouts should their lungs develop abnormally. If the MAGP-2 -/- mice lack an overt phenotype, they will be bred with MAGP-1 knockout mice to make mice lacking both MAGPs to assess whether the MAGPs have overlapping yet critical functions.

描述（申请人摘要）：微原纤维相关糖蛋白-2 (MAGP-2) 是两个 MAGP 之一，两者都是 与弹性纤维相关的微原纤维。 MAGP-2在此显示结合 特别是原纤维蛋白-1 和 -2，这两种特征明确的成分 与遗传性疾病遗传相关的细胞外微纤维 称为马凡综合征和先天性挛缩的弹性纤维 分别是蜘蛛指。 MAGP-2 也绑定 MAGP-1。在本提案中， 将检查微纤维内 MAGP-2 的功能。 MAGP-2 结合 fibrillin-1 和 MAGP-1 上的位点将被本地化，决定因素也将被本地化 MAGP-2 负责这些。 MAGP-2的空间和时间模式 将确定发育中小鼠的基因表达，并且 与其他主要弹性纤维成分的共表达/共定位将 评估。 MAGP-1 敲除小鼠中的 MAGP-2 表达也将 调查了。携带 MAGP-2 基因定向破坏的小鼠将 生成并评估发育异常。微原纤维在 MAGP-2 -/- 小鼠将在超微结构水平上进行研究。如果老鼠死了 在胚胎发育过程中，原代成纤维细胞培养物来源于 MAGP-2 -/- 肺，用于研究 MAGP-2 在微纤维组装中的作用 体外。 MAGP-2 在肺分支形态发生中的作用也将是 如果他们的肺部发育异常，则进行基因敲除研究。如果 MAGP-2 -/- 小鼠缺乏明显的表型，它们将与 MAGP-1 敲除小鼠一起繁殖 让缺乏两个 MAGP 的小鼠来评估 MAGP 是否重叠 关键功能。