A model to study human TLR9 function in mice

描述(申请人提供)：这项研究计划的总体目标是了解人和小鼠Toll样受体9(TLR9)差异的意义。TLR9的特异性及其在免疫细胞中的表达在这些物种中都不同，这使得将TLR9功能的小鼠研究扩展到人类是困难的。在这项提议中，人类TLR9转基因盒将被用来创造表达人TLR9的小鼠品系或具有人类表达模式的小鼠TLR9。TLR9在这些小鼠中的功能将使用一系列标准进行评估。与公共卫生相关：临床上有相当大的兴趣使用Toll样受体9(TLR9)的合成配体来治疗传染病，生产更好的疫苗，并缓解过敏或哮喘的症状。不幸的是，TLR9在人类和小鼠身上的功能差异，使得评估这种方法在非人类灵长类动物以外的动物模型中的有效性变得困难。这项建议的重点是创造和表征“人源化”的TLR9小鼠，这将使人和小鼠之间的TLR9功能比较成为可能。

DESCRIPTION (provided by applicant): The overall goal of this research plan is to understand the significance of differences between human and mouse Toll-like receptor 9 (TLR9). Both the specificity of TLR9 and its expression among immune cells differ between these species, making it difficult to extend mouse studies of TLR9 function into humans. In this proposal, a human TLR9 transgenic cassette will be used to create mouse strains expressing human TLR9 or mouse TLR9 with the human expression pattern. The function of TLR9 in these mice will be evaluated using a number of criteria. PUBLIC HEALTH RELEVANCE: There is considerable clinical interest in using synthetic ligands of Toll-like receptor 9 (TLR9) to treat infectious disease, generate better vaccines, and alleviate symptoms of allergy or asthma. Unfortunately, differences in the function of TLR9 in humans and mice have made it difficult to assess the efficacy of such approaches in animal models other than non-human primates. This proposal focuses on creating and characterizing "humanized" TLR9 mice that will enable the comparison of TLR9 function between humans and mice.