Cellular Signaling by Double-Stranded RNA

双链 RNA 的细胞信号传导

• 批准号: 8052286
• 负责人: GANES C. SEN
• 金额: $ 51.79万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052286
• 关键词: Adaptor Signaling Protein; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biochemical; Cell Migration Inhibition function; Cells; Chronic; Coupled; Disease; Double-Stranded RNA; Epidermal Growth Factor Receptor; Funding; Gene Expression; Genes; Growth Factor Receptors; Host Defense; Immune; Immunologic Receptors; Inflammation; Inflammatory; Inflammatory Response; Injury; Instruction; Leukocytes; Light; Link; Malignant Neoplasms; Maps; Mediating; Modality; NF-kappa B; Natural Immunity; Oncogene Proteins; Phosphorylation; Phosphotransferases; Physiological; Play; Principal Investigator; Property; Protein Tyrosine Kinase; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Stress; TLR3 gene; Testing; Tissues; Toll-like receptors; Tyrosine; Tyrosine Phosphorylation; Virus Diseases; base; cell motility; cell type; gene induction; migration; novel; receptor-mediated signaling; research study; response; sensor; trafficking; transcription factor; tumorigenesis; v-src Oncogenes

Two new mechanisms of suppression of inflammatory responses, mediated by the Toll-like receptor, TLRS and the transcription factor, lRF-3, will be studied at the cellular and organismal levels. TLRS is a sensor of double-stranded RNA and has been studied in the context of immediate innate responses to virus infection. But TLRS can also mediate response to endogenous cellular dsRNAs generated during a vahety of tissue injuries. One ofthe major findings in the current funding period was that the phosphorylation of tyrosine residues in TLRS is essential for its ability to initiate signaling. In specific aim 1, the regulation of Tyr phosphorylation of TLRS will be investigated with emphasis upon the role of the tyrosine-kinase activity of EGF receptors, which were found by us to interact with TLRS. A unique property of TLRS is its exclusive use of the adaptor protein TRIF for the activation of transcription factors IRFS and NFKB. Surprisingly, we have discovered a TRIF-independent activity of TLRS that requires the recruitment and activation of the proto¿¿ oncogene Src and causes inhibition of cell migration. In the second specific aim, the requirements for and consequences of Src activation by TLRS will be defined and the cellular and physiologic consequences will be evaluated. Finally, we have recently observed that IRFS has a significant suppressive effect on the pro¿¿ inflammatory transcription factor, NFKB. The third specific aim will identify the structural features of the two proteins that mediate their physical interaction, and determine the biochemical, cellular and physiologic consequences ofthis interaction. The proposed experiments will test the hypothesis that TLRS and its associated components are coupled with both stimulus (dsRNA) dependent and independent functions that collectively impact upon pro-inflammatory gene expression and trafficking of pro-inflammatory leukocytes. These functions are likely to operate in a cell type and tissue restricted fashion and have significant impact on inflammatory disease and the associated effect on tumorigenesis. Interactions with projects 2, S, 4 and core B will be essential to assess how these functions and their control will impact inflammation related tumongenesis. RELEVANCE (See instructions): Results from the proposed studies will shed light on the anti-inflammatory role of TLRS signaling by inhibiting inflammatory cell migration and that of IRF-S by inhibiting inflammatory gene induction by NFkB. They will also connect the actions of two oncoproteins, Src and EGF receptor, to TLRS signaling, thus revealing a new aspect of interplay between inflammation and cancer.

炎症反应抑制抑制的两种新机制，由Toll样接收器TLRS介导 转录因子LRF-3将在细胞和有机水平上进行研究。 TLR是一个传感器 双链RNA，在对病毒感染的天生反应的背景下已研究。 但是TLR还可以介导对组织vahety产生的内源性细胞DSRNA的反应 受伤。当前资金期间的主要发现之一是酪氨酸的磷酸化 TLR中的残基对于启动信号传导的能力至关重要。在特定的目标1中，对Tyr的调节 将研究TLR的磷酸化，重点是酪氨酸激酶活性的作用 EGF受体，我们发现与TLR相互作用。 TLR的独特属性是其独家使用 转录因子IRF和NFKB激活的衔接蛋白TRIF的含量。令人惊讶的是，我们有 发现了TLR的TRIF非依赖性活性，需要募集和激活原始的活动。 癌基因SRC并引起细胞迁移的抑制。在第二个特定目标中，对 将定义TLR激活SRC的后果，并将细胞和生理后果 进行评估。最后，我们最近观察到，IRFS对Pro€具有重大的抑制作用。 炎症转录因子，NFKB。第三个特定目标将确定两者的结构特征 介导其身体相互作用的蛋白质并确定生化，细胞和生理 这种相互作用的后果。提出的实验将检验TLR及其ITS的假设 相关的成分与刺激（DSRNA）依赖性和独立功能相结合 对促炎的基因表达和促炎性白细胞的运输总体影响。 这些功能可能以细胞类型和组织限制的方式运行，并具有重大影响 关于炎症性疾病及其对肿瘤发生的影响。与项目2，S，4和 核心B对于评估这些功能及其控制将是至关重要的 肿瘤。 相关性（请参阅说明）： 拟议研究的结果将通过抑制TLRS信号的抗炎作用揭示 通过抑制NFKB诱导炎症基因的炎症细胞迁移和IRF-S的迁移。他们会的 还将两个癌蛋白SRC和EGF受体的作用连接到TLRS信号，从而揭示了一个新的 炎症与癌症之间相互作用的方面。