LPS Signaling in Macrophages: The Role of the Toll

描述（由申请人提供）：先天免疫系统是抵御病原体的第一道防线。先天免疫细胞缺乏适应性免疫系统的精致特异性，但为了以一种可测量的方式作出反应，它们必须能够针对特定的病原体做出相应的反应。因此，这些细胞进化出了模式识别受体（PRRs），可以识别微生物的保守分子模式，而这些模式在宿主体内是找不到的。toll样受体（TLRs）和rig - i样受体（rlr）是检测病毒的PRRs。这些受体主要通过诱导I型干扰素来启动抗病毒反应。I型ifn的严格调控是至关重要的，因为细胞因子的过度产生可以显著促进自身免疫性疾病；因此，健康和疾病之间的平衡是由这一途径的精细调节决定的。转录因子IRF7是系统性1型IFN反应的“主调节因子”。虽然人们对IRF7激活的机制了解很多，但对其负面调控知之甚少。系统生物学方法使我们能够确定至少两个IRF7通路的负调节因子：在转录水平上调节IRF7的转录因子Foxo3和转录后调节IRF7网络的microRNA-144 （miR-144）。我们也有证据表明至少有一个额外的miRNA调节IRF7。本研究旨在阐明Foxo3和miR-144调控IRF7的分子机制。它还旨在使用高通量筛选鉴定未知的irf7调节mirna。然后将使用系统方法将Foxo3和mirna整合到全球IRF7调控网络中。最后，我们将研究IRF7- FOXO3-miRNA调控回路在VSV感染小鼠模型中的体内相关性。

DESCRIPTION (provided by applicant): The innate immune system is the first line of defense against pathogens. Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way they must be able to tailor their response to the specific pathogen. These cells have therefore evolved pattern recognition receptors (PRRs) that recognize conserved molecular patterns characteristic of the microbe, which are not found within the host. The Toll-like receptors (TLRs) and the RIG-I-like receptors (RLRs) are the PRRs that detect viruses. These receptors initiate anti-viral responses principally by inducing type I interferons. The tight regulation of type I IFNs is critical since overproduction of the cytokine can contribute significantly to autoimmune disease; thus the balance between health and disease is determined by exquisite regulation of this pathway. The transcription factor IRF7 is a "master regulator" of systemic type 1 IFN responses. While much is known about the mechanisms by which IRF7 is activated little is known about its negative regulation. Systems biology approaches have enabled us to identify at least two negative regulators of the IRF7 pathway: the transcription factor Foxo3 that regulates IRF7 at a transcriptional level and microRNA-144 (miR-144) that regulates the IRF7 network post-transcriptionally. We also have evidence that at least one additional miRNA regulates IRF7. This proposal aims to clarify the molecular mechanisms by which Foxo3 and miR-144 control IRF7. It also aims to identify the unknown IRF7-regulating miRNAs using a high throughput screen. Systems approaches will then be used to integrate Foxo3 and the miRNAs into a global IRF7 regulatory network. Finally, we will examine the in vivo relevance of the IRF7- FOXO3-miRNA regulatory circuit in a mouse model of VSV infection.