Project 1 (Brasier, A.R.)
Allan R. Brasier MD
Nelda C. and H.J. Lutcher Stark
Distinguished Professor in Internal Medicine
Department of Internal Medicine-Endocrinology
Director, Sealy Center for Molecular Sciences
Director, Institute for Translational Sciences
301 University Blvd.
Galveston, TX 77555-1060
Dr. Brasier's bio...
Brasier Lab Website
Sealy Center for Molecular Medicine
Institute for Translational Sciences
The innate immune response (IIR) plays a critical role in the pulmonary host defense. There, cytokine stimulation, viral infection and/or DNA damage/response activate mucosa-resident cells to produce inflammation and antiviral defenses. These pathways are mediated by coordinate induction of nuclear factor-kB (NF-kB)/RelA and interferon response factor (IRF)3 transcription factors. Our previous studies showed inducible reactive oxygen species (ROS) play a critical regulatory role in the IIR. We have found that ROS formation affects phosphorylation at RelA Ser276, a switch required for RelA to complex with the cyclin-dependent kinase (CDK)-9-bromodomain-4 (Brd4) complex. This complex, known as the positive elongation factor-b (PTEF-b), phosphorylates Ser2 of the heptad repeat in the RNA polymerase II C-terminal domain (CTD) to express highly inducible target genes. The mechanisms by which ROS control PTEF-b activity and its role in innate inflammatory and antiviral responses is unknown.
Our long-term goal is to understand the role of the pulmonary IIR in airway disease. Project 1 (P1) seeks to understand the mechanism(s) by which ROS modulate innate signaling in the epithelial cell. We will test the hypothesis that ROS control innate inflammatory and antiviral pathways by promoting the activation of NF-lB/RelA and IRF3 in the airway epithelium. We will investigate key aspects of this central hypothesis by pursuing three Specific Aims, to:
Studies in this project will, for the first time, establish the role of the ROS-initiated transcriptional elongation pathway in inflammatory and antiviral programs downstream of the IIR. Demonstrating that CDK9 is a central mediator of the early innate response in vivo will lay the foundation for novel approaches to selectively modulate inflammation in airway mucosa and RSV bronchiolitis.
- 1. test the hypothesis that ROS modify NF-kB/RelA to induce recruitment of the Brd4-CDK9 complex mediating inflammatory cytokine production;
- 2. test the hypothesis that ROS mediate IRF3 pathway signaling by disrupting its induced enhanceosome;
- 3. test the hypothesis that transcriptional elongation mediates the effect of the IIR in RSV infection in vivo.
- Liu, P, Li, K, Garofalo, RP, and Brasier, AR†. RSV-induces RelA release from cytoplasmic 100 kDa NF-?B2 complexes via a novel retinoic acid inducible gene-I-NF-?B inducing kinase (NIK) signaling pathway. J Biol Chem 283: 23169 – 23178, 2008. PMCID: PMC2516985.
- Jamaluddin, M., Tian, B., Boldogh, I., Garofalo, RP and Brasier, AR. Respiratory Syncyctial Virus Infection Induces A ROS-MSK1-Phospho-Ser-276 RelA Pathway Required For Cytokine Expression. J Virol, 83: 10605-10615, 2009. PMCID: PMC2753134.
- Liu, P, Lu, M, Tian, B, Li, K, Garofalo, RP and Brasier, AR. Expression Of An IKKg Splice Variant Determines IRF3 – Canonical NF-kB Pathway Utilization In ssRNA Virus Infection. PLoS ONE, 4(11): e8079, 2009. PMCID: PMC2778955.
- Jamaluddin, M, Wiktorowicz, JE, Soman, K, Boldogh, S, Forbus, JD, Spratt, H, Garofalo, RP and Brasier AR. Role of Peroxiredoxin-1 and -4 in Protection of RSV-induced Cysteinyl-oxidation of Nuclear Cytoskeletal Proteins. J Virol., 84: 9533-45, 2010. PMCID: PMC20610706.
- Bao, X, Indikuri, H., Liu, T., Liao, S.L., Tian, B., Brasier, AR, Garofalo, R and Casola, A. IKKepsilon modulates RSV-induced NF-kappaB-dependent gene transcription. Virology 408: 224-231, 2010. PMCID: PMC2975836.
- Tian, B, Zhao, Y., Kalita, M., Edeh, M, Paessler, S., Casola, A. Teng, MF, Garofalo, RP and Brasier AR†. CDK9-dependent transcriptional elongation in the innate ISG response to RSV infection in airway epithelial cells. J Virol., in press, 2013
- Brasier, AR, and Calhoun, WJ. Proteomic Insights Into Inflammatory Airway Diseases. Current Proteomics8:84-96, 2011.
- Zhao, Y, and Brasier AR. Applications Of Selected Reaction Monitoring (SRM)-Mass Spectrometry (MS) For Quantitative Measurement Of Signaling Pathways. In “Quantitative Proteomics” Theme Issue. Methods, Elsevier Publishers, 2013 Feb 11. doi:pii: S1046-2023(13)00020-0. 10.1016/j.ymeth.2013.02.001
- Brasier AR. Identification Of Innate Immune Response Endotypes In Asthma: Implications For Personalized Medicine. Current Allergy and Asthma Reports, 2013, in press