Hyper-Responsiveness to TLR Agonists in Wild Derived Mice

促炎细胞因子的释放是宿主病原体防御的关键早期事件，通常限制了 最初通过先天机制传播感染性病原体，并激活适应反应 长期控制或完全消除感染。因为这些免疫过程可能是有害的 对于宿主组织，细胞因子的释放数量和时间过程必须得到精细控制和大量 病理与细胞因子活性失调有关。微调中使用的分子机制 因此，这一过程是积极调查的主题。在这里，我们建议使用正向遗传分析 近交系(C57BL/6J)和野生型(Molf/Ei，捷克/EiII，MSM/MS)小鼠品系分泌不同 IL-6对TLR刺激的反应作为表征早期调节的一种新方法 细胞因子的释放。一组回交小鼠的初步研究已经确定了6号染色体上的两个基因座和 9个对该性状有重大贡献的基因。此外，这两个基因座具有显著的上位性交互作用(p&lt； 10-6，LRS 48.1)。我们的图谱表明，这些基因座包含以前没有涉及到的候选基因 TLR介导的信号转导。我们建议通过减数分裂重组来定位这些基因(并检验这一假设 这些基因座上的等位基因变异对表型有贡献？)我们还建议建立一种机制 他们观察到的上位性相互作用的基础。这项建议旨在通过更精细的方法来解决这个问题。 对候选基因进行遗传分析以及生化和分子表征。我们相信 我们将揭示TLR信号的重要新机制。

The release of pro-inflammatory cytokines is a critical early event in host pathogen defense, often limiting the initial spread of infectious agents through innate mechanisms and activating the adaptive response for more long-term control or complete elimination of infection. Because these immunologic processes can be damaging to host tissue, the amount and time course of cytokine release must be finely controlled and numerous pathologies are associated with dysregulated cytokine activity. The molecular mechanisms used in fine-tuning this process are therefore the subject of active investigation. Here we propose using a forward genetic analysis of inbred (C57BL/6J) and wild derived (MOLF/Ei, Czech/EiII, MSM/Ms) mouse strains that secrete different amounts of IL-6 in response to TLR stimulation as a novel approach to characterizing the regulation of early cytokine release. Initial studies from a panel of backcross mice have identified two loci on chromosomes 6 and 9 that make major contributions to the trait. Further, these two loci have a significant epistatic interaction (p < 10-6, LRS 48.1). Our mapping indicates that these loci contain candidate genes not previously implicated in TLR-mediated signaling. We propose to map these genes via meiotic recombination (and test the hypothesis that allelic variation at these loci contributes to the phenotype?). We also propose to establish the mechanistic basic for their observed epistatic interaction. This proposal aims to approach the problem through more refined genetic analysis as well as biochemical and molecular characterization of the candidate genes. We believe that we will reveal important novel mechanisms of TLR signaling.