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.

促炎性细胞因子的释放是宿主病原体防御中的关键早期事件，通常限制了宿主的免疫应答。 感染因子通过先天机制的最初传播，并激活适应性反应， 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，细胞因子释放的量和时间过程必须被精细地控制， 病理学与失调的细胞因子活性有关。用于微调的分子机制 因此，这一进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（C57 BL/6 J）和野生衍生的（MOLF/Ei、Czech/EiII、MSM/Ms）小鼠品系，其分泌不同的 IL-6对TLR刺激的响应量作为表征早期IL-6调节的新方法。 细胞因子释放来自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， 9、对该性状有重大贡献的。此外，这两个基因座具有显著的上位相互作用（p <0.05）。 10-6，LRS 48.1）。我们的定位表明，这些基因座含有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定位这些基因（并检验假设 这些基因座上的等位基因变异对表型有贡献吗？）我们还建议建立机制 这是观察到的上位相互作用的基础。该建议旨在通过更精细的方法来解决问题。 候选基因的遗传分析以及生物化学和分子表征。我们认为 我们将揭示TLR信号传导的重要新机制。