Hyper-Responsiveness to TLR Agonists in Wild Derived Mice

野生小鼠对 TLR 激动剂的过度反应

• 批准号: 7683460
• 负责人: Alexander Poltorak
• 金额: $ 41.15万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2009-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683460
• 关键词: Acute-Phase Proteins; Address; Affect; Agonist; Alleles; Amino Acids; Area; Back; Backcrossings; Biochemical; Breeding; Candidate Disease Gene; Chromosome Mapping; Chromosomes, Human, Pair 6; Comparative Study; Data; Data Linkages; Defect; Detection; Disease; Ectopic Expression; Event; Family; Genes; Genetic Epistasis; Genetic Polymorphism; Genetic Transcription; Goals; Hour; Hybrids; IL6 gene; IRAK1 gene; IRAK2 gene; Immune response; Immunologics; Individual; Infection; Infectious Agent; Inflammatory; Interleukin-6; Investigation; LTA gene; Link; MSM/Ms Mouse; Maps; Mediating; Meiotic Recombination; Messenger RNA; Minor; Modeling; Molecular; Mouse Strains; Mus; Mutation; Pathology; Pathway interactions; Phenotype; Process; Proteins; Regulation; Reporting; Resolution; Role; Series; Signal Pathway; Signal Transduction; Specificity; Sum; Testing; Time; Tissues; Transcriptional Activation; Tumor Necrosis Factor-Beta; Variant; base; chromatin remodeling; congenic; cytokine; genetic analysis; genetic linkage analysis; improved; in vivo; interest; macrophage; member; novel; novel strategies; pathogen; promoter; protein protein interaction; response; trait

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.

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 传染源通过先天机制的初始传播并激活适应性反应以实现更多 长期控制或完全消除感染。因为这些免疫过程可能会造成损害 对于宿主组织，细胞因子释放的量和时间过程必须受到精细控制并且数量众多 病理与细胞因子活性失调有关。用于微调的分子机制 因此，这一过程受到积极调查。在这里我们建议使用正向遗传分析 近交 (C57BL/6J) 和野生衍生 (MOLF/Ei、捷克/EiII、MSM/Ms) 小鼠品系分泌不同的 响应 TLR 刺激的 IL-6 量作为表征早期调节的新方法 细胞因子释放。一组回交小鼠的初步研究已经确定了 6 号染色体和 6 号染色体上的两个基因座。 9 对特质做出重大贡献的人。此外，这两个位点具有显着的上位相互作用（p < 10-6，LRS 48.1）。我们的作图表明这些基因座包含先前未涉及的候选基因 TLR 介导的信号传导。我们建议通过减数分裂重组来绘制这些基因的图谱（并检验假设 这些位点的等位基因变异对表型有贡献吗？）。我们还建议建立机制 为观察到的上位相互作用奠定了基础。该提案旨在通过更精细的方式解决该问题 遗传分析以及候选基因的生化和分子表征。我们相信 我们将揭示 TLR 信号传导的重要新机制。