PROJECT 1: CORE COMPONENT OF THE TRAUMA CENTER - ANIMAL CORE II: TRANSGENIC

项目 1：创伤中心的核心组成部分 - 动物核心 II：转基因

• 批准号: 6674467
• 负责人: Michael Craig Carroll
• 金额: $ 15.69万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6674467
• 关键词: animal care; biomedical facility; complement; gene expression; gene targeting; genetically modified animals; injury; ischemia; laboratory mouse; reperfusion

Mouse models have proven very effective in clarifying our understanding of human disease. In particular, the development of mice bearing transgenes or mutations in which specific loci are silenced have lead to identification of novel pathways and mechanisms. During the past funding period, the use of knock-out mice has revealed the importance of IgM natural antibody and complement in induction of ischemia-reperfusion injury. The goal of the animal core in the current proposal is to extend the studies by continuing to maintain and breed mice bearing specific deficiencies in C3, C4 and Cr2 and to generate new strains of mutant mice in which the immunoglobulin loci are modified using a gene targeting approach. Specifically, the animal core will establish transgenic (knock-in) mice in which a rearranged IgH (cm22Hi) and IgL (cm22Li) specific for ischemia antigen are inserted into the respective loci. In addition, mice bearing a mutation within the C/mu domain (IgM c1q-) will be established such that IgM no longer binds and activates Clq. IgM ctq- mice will be important in testing the hypothesis that IgM mediates ischemia-reperfusion injury via complement Clq. Both the complement deficient and the new strains of immunoglobulin mutant mice are critical for continuation of the study of the pathogenesis of I/R injury and will be shared among the different projects. In summary, the animal core not only provides novel strains of mice for extending our current studies on the biology of reperfusion -injury but also provides a critical link among the different projects of the Program Project.

事实证明，小鼠模型对于阐明我们对人类疾病的理解非常有效。特别是，携带特定位点被沉默的转基因或突变的小鼠的发育导致了新途径和机制的鉴定。在过去的资助期间，基因敲除小鼠的使用揭示了IgM天然抗体和补体在诱导缺血再灌注损伤中的重要性。动物核心的目标 目前的建议是通过继续维持和繁殖具有 C3、C4 和 Cr2 特定缺陷的小鼠来扩展研究，并产生新的突变小鼠品系，其中使用基因靶向方法修改免疫球蛋白位点。具体来说，动物核心将建立转基因（敲入）小鼠，其中将缺血抗原特异性的重排 IgH (cm22Hi) 和 IgL (cm22Li) 插入各自的基因座。此外，将建立 C/mu 结构域 (IgM c1q-) 内带有突变的小鼠，使得 IgM 不再结合并激活 Clq。 IgM ctq-小鼠对于检验IgM通过补体Clq介导缺血再灌注损伤的假设非常重要。补体缺陷小鼠和免疫球蛋白突变小鼠的新品系对于继续研究至关重要 I/R 损伤的发病机制并将在不同项目之间共享。 总之，动物核心不仅为扩展我们目前对再灌注损伤生物学的研究提供了新的小鼠品系，而且还为该计划项目的不同项目之间提供了关键的联系。