Gene Regulation in Innate Immunity

 描述（由申请人提供）：先天免疫应答通过驱动炎症、宿主防御途径和适应性免疫来对抗感染性微生物。不同功能类别内的多个基因通过转录“开”和“关”开关协调地和暂时地调节，所述转录“开”和“关”开关解释响应于微生物触发物的基因表达的特异性。明确定义的DNA结合转录因子、转录辅助调节因子和染色质修饰复合物协作以协调免疫基因的转录。 该提案将集中于两种基因表达调节因子：CCHC型锌指，称为胞质核酸结合蛋白（CNBP）的核酸结合蛋白和称为lincRNA-Cox 2的非编码基因。Aim 1的重点是了解CNBP（一种易位到细胞核的TBK 1相互作用蛋白）如何控制I型IFN基因转录以及这种蛋白在控制病毒感染中的作用。目的1将使用新产生的CNBP缺陷小鼠确定CNBP有助于体内炎症基因转录调控和宿主防御的分子基础。 目的2和3建立在我们的发现基础上，即长非编码RNA（lincRNA-Cox 2）调节先天免疫细胞中I型IFN和炎症基因的表达3。lncRNA正在成为包括免疫在内的多种生物学环境中基因表达的重要调节因子15。Aim 2将定义炎症基因表达的lincRNA-Cox 2依赖性控制的分子基础。Aim 3将利用新产生的lincRNA-Cox 2缺陷小鼠来定义lincRNA-Cox 2在体内的作用。 总的来说，这些研究将检验CNBP和lincRNA-Cox 2代表先天免疫应答的新调节组分的假设。我们提出CNBP在控制PRR激活的途径中的I型IFN的转录中是重要的，在PRR激活的途径中，CNBP充当TBK 1-IRF 3激活的调节剂和/或其易位到细胞核后的基因转录的调节剂。此外，我们提出lincRNA-Cox 2通过结合染色体位点和募集转录因子或染色质修饰复合物来控制基因转录，从而控制细胞核中的基因表达。 CNBP如何调控炎症基因转录的详细机制研究以及lincRNA-Cox 2的作用，其蛋白质伴侣和基因组靶点的阐明将提供关键的见解，可能会导致感染性和自身免疫性疾病的改进治疗方法的发展。

 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.