The long-term objective of this project is to understand the role of protein kinase R (PKR) in the regulation of signaltransduction 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 ligandsincluding dsRNA, tumor necrosis factor (TNF) and IFN-y via its interaction with ItcB kinase. The engagement of theType 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. PAMPengagement of TLRs also activates PKR-dependent regulation of the production of pro-inflammatory cytokines via amitogen activated protein kinase (MAPK) pathway where PKR interacts with MAP kinase kinase 6 (MKK6). Ourdiscoveries 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 proposeto provide a better understanding of the molecular determinants that regulate these pathways. More specifically we willfocus on the role of PKR as a key signaling molecule that can be invoked by IFNs, cytokines, and PAMPs to signaldifferent transcription factors regulating gene expression. We will achieve this by the following specific aims. We willestablish the molecular determinants that define PKR as a key regulator of MAPK signaling pathways. We willinvestigate the mechanisms of p53 instability induced by dsRNA and characterize the signaling.pathway by which thisis achieved. We will define the mechanisms of synergy between dsRNA and CpG ODN by investigating the role oftype I IFNs, dsRNA signaling pathways, and components of the TLR signaling pathway required to mediate thesynergistic response. We will also determine whether the synergy results in enhanced tumor immunity in vivo andestablish the relative contribution of the dsRNA-activated pathways. These studies have the potential to provide insightinto the regulation of innate immunity and its exploitation in cancer therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Subcommittee G - Education (NCI)
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Cleveland Clinic Lerner
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