DEVELOPMENT AND CHARACTERIZATION OF CD14 DEFICIENT MICE

描述(改编自申请者的摘要)：CD14是一个55 kDa的 糖基磷脂酰肌醇连接的蛋白，也存在于可溶性 在血清中形成。CD14结合来源于 革兰氏阴性细菌的最外层，并激活一个信号级联 这会导致包括肿瘤在内的炎症细胞因子的产生 肿瘤坏死因子α、白介素6和白介素1。这一回应具有 已证明在革兰素史克继发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发展和在 促进组织学标志--巨噬细胞泡沫细胞的形成 早期动脉粥样硬化的特征。有几条证据也证明了这一途径 在前列腺癌的发病机制中，不孕不育的主要原因在发达国家 世界上，在吞噬凋亡细胞的过程中，这是 组织重塑和发育。研究人员致力于炎症性疾病 肠病、牙周病、各种肺炎性疾病 疾病也推测CD14在这些疾病中起着重要作用。 鉴于人们对了解CD14对 正常生理和病理条件，申请人的实验室有 产生了缺乏该蛋白的同源重组小鼠。这笔赠款 应用程序建议产生这些动物的繁殖群体，并 将这些老鼠分发给要求它们的许多调查人员。 这些研究人员致力于疾病的研究，得到了美国国立卫生研究院不同组织的支持 研究所，然后可以利用这些动物在实验中探索 涉及CD14活性的生物过程。此外 为了发展CD14缺陷小鼠的繁育群体，这一应用 建议将这些动物作为疾病模型的用途 它们代表着主要的人类健康问题，其中主要的 该基金的调查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老鼠品系 以探讨衣原体感染在动脉粥样硬化发病中的作用 心血管疾病的发病机制。此外，CD14基因缺失的小鼠也将 用于探讨内毒素信号通路在小鼠模型中的作用 控制系统的性能。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性疾病并使 这是调查界普遍可用的重要动物资源。

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.