DEVELOPMENT AND CHARACTERIZATION OF CD14 DEFICIENT MICE

描述（改编自申请人的摘要）：CD 14是一个55 kDa的 糖基磷脂酰肌醇连接蛋白，也存在于可溶性 形成血清。 CD 14结合来源于细胞的脂多糖（LPS）。 革兰氏阴性菌的最外层，并激活信号级联 导致炎症细胞因子的产生， 坏死因子α、白细胞介素-6和白细胞介素-1。 这一回应 在革兰氏阴性菌感染后脓毒性休克的发病机制中具有重要作用， 阴性败血症。 最近的数据也表明， 可能在加速动脉粥样硬化斑块的发展和 促进巨噬细胞泡沫细胞的形成， 早期动脉粥样硬化 一些证据也暗示了这一途径 在PID的发病机制，不孕症的主要原因，在发达国家 世界，并在吞噬凋亡细胞，一个重要的事件， 组织重塑和发育。 研究人员正在研究 肠道疾病、牙周病和各种炎症性肺部疾病 疾病也假定了CD 14在这些病症中的重要作用。 鉴于人们对了解CD 14对人类免疫功能的贡献的广泛兴趣， 在正常的生理和病理条件下，申请人的实验室 产生了缺乏这种蛋白质的同源重组小鼠。 这笔赠款 本申请提出产生这些动物的繁殖群体， 将这些老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美国国立卫生研究院不同小组支持的疾病， 研究所，然后可以利用这些动物在实验中，探索 其中涉及CD 14活性的生物过程。 此外 本申请涉及开发CD 14缺陷小鼠的繁殖群体， 提出了这些动物作为疾病模型的特点， 这些问题代表了人类的主要健康问题， 该补助金的调查人员已经建立了研究工作。 因此，CD 14 缺陷动物将被培育成容易感染的小鼠品系 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，CD 14-null小鼠也将 用于探索内毒素信号通路在小鼠模型中的作用 的PID。 这项工作旨在扩大CD 14缺陷的适用性， 小鼠研究涉及急性和慢性炎症性疾病， 对整个调查界来说是一种重要的动物资源。

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.