Alternate Pathways for Interferon and Cytokine Signaling

这个项目的长期目标是了解蛋白激酶R(PKR)在信号调节中的作用 干扰素(IFN)、细胞因子和病原体相关分子模式激活的转导通路 (PAMPS)通过Toll样受体(TLRs)传递信号。PKR通过不同的配体调节核因子-TCB通路中的信号 包括dsRNA、肿瘤坏死因子(TNF)和干扰素-γ通过其与ItcB激酶的相互作用。该项目的参与度 I型和II型干扰素受体还可以导致PKR调节胞浆cPLA2和他汀类丝氨酸的磷酸化。 此外，STAT3酪氨酸和丝氨酸的磷酸化可以通过依赖PKR的途径来调节。PAMP TLRs的参与也激活了PKR依赖的对促炎细胞因子的产生的调节 丝裂原活化蛋白激酶(MAPK)途径，其中PKR与MAPK6(MKK6)相互作用。我们的 发现dsRNA可以调节抑癌基因P53的稳定性，dsRNA和CpG寡核苷酸 (CPG ODN)在促炎细胞因子产生中的协同作用使人们对PKR的作用产生了疑问。我们建议 以便更好地了解调控这些途径的分子决定因素。更确切地说，我们将 重点关注PKR作为一个关键信号分子的作用，它可以被IFN、细胞因子和PAMP激活以进行信号传递 不同的转录因子调节基因表达。我们将通过以下具体目标实现这一目标。我们会 确定将PKR定义为MAPK信号通路的关键调节因子的分子决定因素。我们会 研究dsRNA诱导P53不稳定的机制并表征其信号转导途径。 已经实现了。我们将通过研究dsRNA和CpG ODN之间的作用来确定dsRNA和CpG ODN之间的协同机制 I型IFN、dsRNA信号通路和TLR信号通路的组成部分 协同反应。我们还将确定这种协同作用是否会导致体内肿瘤免疫增强和 确定dsRNA激活途径的相对贡献。这些研究具有提供洞察力的潜力 探讨先天免疫的调节及其在癌症治疗中的应用。

The long-term objective of this project is to understand the role of protein kinase R (PKR) in the regulation of signal transduction pathways activated by interferons (IFNs), cytokines, and the pathogen associated molecular patterns (PAMPS) signaling via Toll like receptors (TLRs). PKR regulates signaling in the NF-tcB pathway by different ligands including dsRNA, tumor necrosis factor (TNF) and IFN-y via its interaction with ItcB kinase. The engagement of the Type I and type IIIFN receptors can also lead to PKR regulation of cytosolic cPLA2 and Statl serine phosphorylation. In addition, Stat3 tyrosine and serine phosphorylation can be regulated via a PKR-dependent pathway. PAMP engagement of TLRs also activates PKR-dependent regulation of the production of pro-inflammatory cytokines via a mitogen activated protein kinase (MAPK) pathway where PKR interacts with MAP kinase kinase 6 (MKK6). Our discoveries that dsRNA can regulate tumor suppressor p53 stability and that dsRNA and CpG oligodeoxynucleotides (CpG ODN) can synergize in pro-inflammatory cytokine production raises questions about a role for PKR. We propose to provide a better understanding of the molecular determinants that regulate these pathways. More specifically we will focus on the role of PKR as a key signaling molecule that can be invoked by IFNs, cytokines, and PAMPs to signal different transcription factors regulating gene expression. We will achieve this by the following specific aims. We will establish the molecular determinants that define PKR as a key regulator of MAPK signaling pathways. We will investigate the mechanisms of p53 instability induced by dsRNA and characterize the signaling.pathway by which this is achieved. We will define the mechanisms of synergy between dsRNA and CpG ODN by investigating the role of type I IFNs, dsRNA signaling pathways, and components of the TLR signaling pathway required to mediate the synergistic response. We will also determine whether the synergy results in enhanced tumor immunity in vivo and establish the relative contribution of the dsRNA-activated pathways. These studies have the potential to provide insight into the regulation of innate immunity and its exploitation in cancer therapy.