Development of humanized TLR4 SNP mouse models

描述（由申请人提供）：文献中的当前数据提供了关于人Toll样受体4（TLR 4）单核苷酸多态性（SNP）与多种疾病（包括败血症、脑膜炎球菌病、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、类风湿性关节炎、恶性黑色素瘤和代谢综合征）相关性的相互矛盾的结果。由于缺乏合适的动物模型，对人类TLR 4 SNP在这些不同疾病中的作用的分析受到阻碍。我们最近开发了一种新的转基因小鼠模型，编码人类而不是小鼠TLR 4及其辅助受体MD-2。这种新的转基因小鼠比传统小鼠对革兰氏阴性细菌感染表现出更多的类似人类的反应。在这项R21资助申请中，我们建议将我们的研究扩展到表达最常见的人类TLR 4变体（即TLR 4D 299 G和TLR 4D 299 G + T399 I）的新生成的细胞系。这里获得的结果将确定这些新的TLR 4 SNP小鼠是否可以有益于研究大范围的感染性和非感染性疾病，其中TLR 4 SNP关联已被描述。

DESCRIPTION (provided by applicant): 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.