LPS Signaling in Macrophages: The Role of the Toll

描述（由申请人提供）：先天免疫系统是抵抗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确特异性，但为了以可测量的方式做出反应，它们必须能够针对特定病原体调整其反应。因此，这些细胞已经进化出模式识别受体（PRR），其识别微生物特有的保守分子模式，这在宿主中没有发现。Toll样受体（TLR）和RIG-I样受体（RLR）是检测病毒的PRR。这些受体主要通过诱导I型干扰素来启动抗病毒应答。I型IFN的严格调节是至关重要的，因为细胞因子的过度产生可显著促进自身免疫性疾病;因此健康与疾病之间的平衡由该途径的精细调节决定。转录因子IRF 7是系统性1型IFN应答的“主调节因子”。虽然对IRF 7的激活机制了解很多，但对其负调控知之甚少。 系统生物学方法使我们能够确定IRF 7通路的至少两个负调节因子：在转录水平调节IRF 7的转录因子Foxo 3和在转录后调节IRF 7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IRF 7。该提案旨在阐明Foxo 3和miR-144控制IRF 7的分子机制。它还旨在使用高通量筛选来鉴定未知的IRF 7调节miRNA。然后将使用系统方法将Foxo 3和miRNA整合到全球IRF 7调控网络中。最后，我们将在VSV感染的小鼠模型中研究IRF 7-FOXO 3-miRNA调控回路的体内相关性。 公共卫生相关性：正在研究的蛋白质在调节人体免疫反应中起着关键作用。它们指导身体有效地对抗传染病，了解它们的功能将使我们能够制造更好的疫苗和药物。然而，这些分子是一把双刃剑。当它们功能不正确时，它们会导致炎症和自身免疫性疾病。了解这是如何发生的将导致设计和生产更好的药物治疗类风湿性关节炎等疾病。

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. PUBLIC HEALTH RELEVANCE: The proteins that are being investigated have a pivotal role in regulating the immune response in people. They instruct the body to effectively combat infectious disease, and an understanding of their function will permit us to make better vaccines and drugs. However, these molecules are a two-edged sword. When they function incorrectly they lead to inflammatory and autoimmune diseases. Understanding how this happens will lead to the design and production of better drugs for diseases such as rheumatoid arthritis.