Gene Regulation in Innate Immunity

 描述(由申请人提供)：先天免疫反应通过驱动炎症、宿主防御途径和适应性免疫来对抗感染微生物。不同功能类别中的多个基因由转录的“开”和“关”开关协调和时间地调节，这些开关解释了基因表达对微生物触发的特异性。明确定义的DNA结合转录因子、转录共调控因子和染色质修饰复合体相互协作，协调免疫基因的转录。这项建议将集中在两个基因表达的调节：CCHC类型的锌指，称为胞浆核酸结合蛋白(CNBP)的核酸结合蛋白和一个非编码基因称为lincRNA-COX2。AIM1的重点是了解CNBP，一种与TBK1相互作用的蛋白是如何控制I型干扰素基因转录的，以及这种蛋白在控制病毒感染中的作用。目的1利用新产生的CNBP缺陷小鼠，确定CNBP在体内对炎症基因的转录调控和宿主防御做出贡献的分子基础。AIM2和3建立在我们的发现基础上，即一个长的非编码RNA(lincRNA-COX2)调节先天性免疫细胞中I型干扰素和炎症基因的表达3。在包括免疫在内的各种生物环境中，lncRNAs正在成为基因表达的重要调节器15。AIM2将定义依赖lincRNA-COX2调控炎症基因表达的分子基础。AIM3将利用新产生的lincRNA-COX2缺陷小鼠来确定lincRNA-COX2在体内的作用。总而言之，这些研究将检验CNBP和lincRNA-COX2代表先天性免疫反应的新调节成分的假设。我们认为，在由PRRs激活的途径中，CNBP在控制I型IFN的转录方面发挥着重要作用，在PRRs激活的途径中，CNBP既是TBK1-IRF3激活的调节因子，也是基因转位到细胞核时的转录调节因子。此外，我们认为lincRNA-COX2通过结合染色体位点和招募转录因子或染色质修饰复合体来控制基因转录，从而控制核内基因的表达。对CNBP如何调控炎症基因转录的详细机制研究，以及lincRNA-COX2及其蛋白伙伴的作用，以及基因组靶点的阐明，将提供关键的见解，可能有助于改进传染病和自身免疫性疾病的治疗方法。

 DESCRIPTION (provided by applicant): Innate immune responses combat infectious microbes by driving inflammation, host-defense pathways and adaptive immunity. Multiple genes within distinct functional categories are coordinately and temporally regulated by transcriptional "on" and "off" switches that account for the specificity of gene expression in response to microbial triggers. Well-defined DNA binding transcription factors, transcriptional co-regulators and chromatin modifying complexes collaborate to coordinate transcription of immune genes. This proposal will focus on two regulators of gene expression: a CCHC-type zinc finger, nucleic acid binding protein termed cytosolic nucleic acid binding protein (CNBP) and a non-coding gene called lincRNA- Cox2. Aim1 is focused on understanding how CNBP, a TBK1 interacting protein that translocates to the nucleus controls type I IFN gene transcription and the role of this protein in controlling virus infection. Aim 1 will determine the molecular bass by which CNBP contributes to transcriptional regulation of inflammatory genes and host-defense in vivo using newly generated CNBP-deficient mice. Aim2 and 3 build on our findings that a long non-coding RNA (lincRNA-Cox2) regulates type I IFN and inflammatory gene expression in innate immune cells3. lncRNAs are emerging as important regulators of gene expression in diverse biological contexts including immunity15. Aim2 will define the molecular basis of lincRNA- Cox2 dependent control of inflammatory gene expression. Aim3 will utilize newly generated lincRNA-Cox2-deficient mice to define the role of lincRNA-Cox2 in vivo. Collectively these studies will test the hypothesis that CNBP and lincRNA-Cox2 represent novel regulatory components of the innate immune response. We propose that CNBP is important in controlling the transcription of type I IFNs in pathways activated by PRRs where it acts either as a regulator of TBK1-IRF3 activation and/or a regulator of gene transcription upon its translocation to the nucleus. In addition, we propose that lincRNA-Cox2 controls gene expression in the nucleus by binding chromosomal loci and recruiting transcription factors or chromatin-modifying complexes to control gene transcription. Detailed mechanistic studies of how inflammatory gene transcription is regulated by CNBP and the role of lincRNA-Cox2, its protein partners and elucidation of genomic targets will provide critical insights that could potentially lead to the development of improved therapeutics for infectious and autoimmune diseases.