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.
The immune system provides protection against invading pathogens, but these immune defenses can also be dangerous and destructive leading to tissue damage resulting in heart disease, arthritis and cancer. It is essential that these inflammatory pathways are carefully regulated to avoid excessive inflammation. It is now clear that both proteins as well as RNA molecules work together to regulate these responses. Long noncoding RNA (lncRNA) are one type of RNA molecule which regulate the expression of other protein coding genes. The studies proposed in this application are focused on understanding the role of protein regulators and non-coding RNA regulates which control the inflammatory response. By identifying how these regulators work we can begin to understand how inflammatory gene expression is regulated. A better understanding of these events is needed to boost immunity for vaccines or to help design drugs to prevent heart disease, arthritis and cancer.
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|Carpenter, Susan; Fitzgerald, Katherine A (2018) Cytokines and Long Noncoding RNAs. Cold Spring Harb Perspect Biol 10:|
|Schrum, Jacob E; Crabtree, Juliet N; Dobbs, Katherine R et al. (2018) Cutting Edge: Plasmodium falciparum Induces Trained Innate Immunity. J Immunol 200:1243-1248|
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|O'Donnell, Joanne A; Lehman, Jesse; Roderick, Justine E et al. (2018) Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity. J Immunol 200:737-748|
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