Development of humanized TLR4 SNP mouse models

7.项目摘要/摘要： 目前文献中的数据提供了关于人类关联性的相互矛盾的结果 Toll样受体4(TLR4)单核苷酸多态性(SNP)和多种 疾病，包括败血症、脑膜炎双球菌病、脑型疟疾、克罗恩病、 溃疡性结肠炎，呼吸道合胞病毒，动脉粥样硬化，类风湿关节炎， 恶性黑色素瘤和代谢综合征。人TLR4基因的功能分析 由于缺乏合适的动物，这些不同疾病中的SNPs受到了阻碍 模特。我们最近开发了一种新的转基因小鼠模型，它可以编码 人而不是小鼠的TLR4及其辅助受体MD-2。这种新的转基因 Line对革兰氏阴性细菌感染的反应比 传统的小鼠。在这份R21拨款申请中，我们建议将我们的研究扩展到 新生成的表达最常见的人类TLR4变异体的行，即 TLR4D299G和TLR4D299G+T399I。在这里获得的结果将决定这些 新型TLR4单核苷酸多态小鼠可用于大范围感染性疾病的研究 以及已描述TLR4 SNP关联的非传染性疾病。

7. PROJECT SUMMARY/ABSTRACT: The current data in the literature provide conflicting results on the association of human Toll-like receptor 4 (TLR4) single nucleotide polymorphisms (SNP) and a variety of diseases, including sepsis, meningococcal disease, cerebral malaria, Crohn's disease, ulcerative colitis, respiratory syncytial virus, atherosclerosis, rheumatoid arthritis, malignant melanoma, and metabolic syndrome. Analysis of the role of human TLR4 SNPs in these diverse diseases has been hampered by the lack of a suitable animal model. We have recently developed a new transgenic mouse model that encodes human rather than mouse TLR4 as well as its coreceptor MD-2. This new transgenic line displays more human-like responses to Gram-negative bacterial infections than conventional mice. In this R21 grant application, we propose to extend our studies to newly generated lines expressing the most common human TLR4 variants, namely TLR4D299G and TLR4D299G+T399I. Results obtained here will determine whether these novel TLR4 SNP mice could be of benefit for the study of the large range of infectious and non-infectious diseases where TLR4 SNP associations have been described.