Alternate Pathways for Interferon and Cytokine Signaling

本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 由干扰素（IFN）、细胞因子激活的转导途径和病原体相关分子模式 （PAMPS）通过Toll样受体（TLR）信号传导。PKR通过不同配体调节NF-tcB通路中的信号传导 包括dsRNA、肿瘤坏死因子（TNF）和IFN-γ，通过其与ItcB激酶的相互作用。的接合 I型和III型IFN受体也可导致胞质cPLA 2和Statl丝氨酸磷酸化的PKR调节。 此外，Stat 3酪氨酸和丝氨酸磷酸化可以通过PKR依赖性途径调节。PAMP TLR的参与也通过激活PKR依赖性调节促炎细胞因子的产生， 丝裂原活化蛋白激酶（MAPK）途径，其中PKR与MAP激酶激酶6（MKK 6）相互作用。我们 发现dsRNA可以调节肿瘤抑制因子p53的稳定性，并且dsRNA和CpG寡脱氧核苷酸 (CpG ODN）可以协同促炎细胞因子的产生，这引起了关于PKR作用的问题。我们提出 以提供对调节这些途径的分子决定因素的更好理解。更具体地说， 关注PKR作为一种关键信号分子的作用，它可以被IFN、细胞因子和PAMP激活， 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。我们将 确定PKR作为MAPK信号通路关键调节因子的分子决定因素。我们将 研究dsRNA诱导的p53不稳定性的机制，并表征其信号通路。 实现了。我们将通过研究dsRNA和CpG ODN之间的协同作用， I型IFN、dsRNA信号传导途径和TLR信号传导途径的组分需要介导 协同反应。我们还将确定协同作用是否导致体内增强的肿瘤免疫， 确定dsRNA激活途径的相对贡献。这些研究有可能提供洞察力， 天然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.