DEVELOPMENT AND CHARACTERIZATION OF CD14 DEFICIENT MICE

CD14 缺陷小鼠的发育和表征

• 批准号: 6199676
• 负责人: MASON W FREEMAN
• 金额: $ 55.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6199676
• 关键词: CD14 molecule; Chlamydia trachomatis; Chlamydiaceae; animal breeding; atherosclerosis; atherosclerotic plaque; bacteria infection mechanism; bacterial pneumonia; chronic disease /disorder; disease /disorder model; endotoxins; gene targeting; genetic mapping; genetic strain; genetically modified animals; genome; laboratory mouse; leukocyte activation /transformation; macrophage; model design /development; pathologic process; pelvic inflammatory disease; phenotype; urinary tract

DESCRIPTION (Adapted from the applicant's abstract): CD14 is a 55 kDa glycosyl phosphatidylinositol-linked protein that is also present in a soluble form in serum. CD14 binds lipopolysaccharides (LPSs) derived from the outermost layer of Gram-negative bacteria and activates a signaling cascade that results in the production of inflammatory cytokines that include tumor necrosis factor alpha, interleukin-6, and interleukin-1. This response has been shown to be important in the pathogenesis of septic shock following Gram- negative septicemia. Recent data have also suggested that a similar response may play a role in accelerating atherosclerotic plaque development and in enhancing the formation of the macrophage foam cell, the histologic hallmark of the early atheroma. Several lines of evidence also implicate this pathway in the pathogenesis of PID, a leading cause of infertility in the developed world, and in the phagocytosis of apoptotic cells, an essential event in tissue remodeling and development. Investigators working on inflammatory bowel disease, periodontal disease, and a variety of inflammatory pulmonary disorders have also postulated an important role for CD14 in these conditions. Given the widespread interest in understanding the contributions of CD14 to normal physiology and pathologic conditions, the applicant's laboratory has generated homologous recombinant mice lacking this protein. This grant application proposes to generate a breeding colony of these animals and to distribute these mice to the many investigators that have requested them. These investigators, working on diseases supported by a diverse group of NIH Institutes, can then utilize these animals in experiments that explore the biological processes in which CD14 activity has been implicated. In addition to developing the breeding colony of CD14 deficient mice, this application proposes to characterize the utility of these animals as models for diseases that represent major human health problems in which the principal investigators of the grant have established research efforts. Thus, the CD14 deficient animals will be bred into mouse strains that are susceptible to atherosclerosis in order to explore the role of Chlamydial infections in the pathogenesis of cardiovascular disease. In addition, CD14-null mice will also be used to explore the role of the endotoxin signaling pathway in mouse models of PID. This work is intended to broaden the applicability of CD14 deficient mice to research involving acute and chronic inflammatory disease and to make a critical animal resource available to the investigative community at large.

描述（改编自申请人的摘要）：CD14 是 55 kDa 糖基磷脂酰肌醇连接蛋白，也存在于可溶性 在血清中形成。 CD14 结合脂多糖 (LPS)，该脂多糖源自 革兰氏阴性细菌的最外层并激活信号级联 导致炎症细胞因子的产生，包括肿瘤 坏死因子 α、白细胞介素 6 和白细胞介素 1。 这个回应有 已被证明在革兰氏阴性菌感染性休克的发病机制中起重要作用 阴性败血症。 最近的数据也表明类似的反应 可能在加速动脉粥样硬化斑块的形成和 增强巨噬细胞泡沫细胞的形成，这是组织学标志 早期动脉粥样硬化。 几条证据也暗示了这一途径 PID 的发病机制是发达国家不孕不育的主要原因 世界，在凋亡细胞的吞噬作用中，这是一个重要的事件 组织重塑和发育。 研究人员致力于炎症研究 肠道疾病、牙周病以及各种肺部炎症 CD14 在这些疾病中也发挥着重要作用。 鉴于人们对理解 CD14 的贡献的广泛兴趣 正常的生理和病理条件，申请人的实验室有 产生了缺乏这种蛋白质的同源重组小鼠。 这笔补助金 申请建议建立这些动物的繁殖群体并 将这些小鼠分发给许多需要它们的研究人员。 这些研究人员致力于研究由 NIH 不同小组支持的疾病 然后，研究所可以利用这些动物进行实验来探索 CD14 活性涉及的生物过程。 此外 为了开发 CD14 缺陷小鼠的繁殖群体，该应用 提议描述这些动物作为疾病模型的效用 代表重大人类健康问题，其中主要 该赠款的研究人员已经开展了研究工作。 因此，CD14 有缺陷的动物将被培育成易受感染的小鼠品系 动脉粥样硬化，以探讨衣原体感染在动脉粥样硬化中的作用 心血管疾病的发病机制。 此外，CD14缺失小鼠也会 用于探索内毒素信号通路在小鼠模型中的作用 PID。 这项工作旨在扩大 CD14 缺陷的适用性 小鼠研究涉及急性和慢性炎症疾病并制造 可供整个研究界使用的重要动物资源。