My major research interests are to understand the mechanisms and contributory role of innate inflammation in chronic human disease. The primary focus of this work has been on mucosal diseases in the airways, with a developing interest in GI inflammation. The innate response is the first line of defense in a stereotypic intracellular signaling pathway triggered by a variety of “nonspecific” ligands, including pathogen associated molecular patterns, death receptors and reactive oxygen species. Our studies have demonstrated the central role of NFkB in activating transcriptional elongation to mediate the innate response, and its consequences in controlling cellular reprogramming, cell state transition and remodeling/fibrosis. I believe this is a fundamental discovery that has significant translational implications. For clarity, I will describe major questions and experimental approaches for the three interrelated projects that constitute the major focus of my research investigation.
1. Innate signaling in viral induced airway disease. A majority of my effort has focused on elucidating intracellular signal transduction pathways mediating cellular response to stress. In a series of collaborative experiments, we were the first to demonstrate the effect of RSV replication on NFkB translocation in infected epithelial cells. Our group has contributed to this exploding field through studying mechanisms controlling trans-activation of the NFkB transcription factor by identification of ribosomal S6 kinases that phosphorylate Ser 276; we have found that RS6Ks are stimulus-specific and oxidative stress-dependent. We were the first to demonstrate that the ROS signaling pathway is mediated by DNA damage response, via the ATM and oxoguanine DNA glycosylase, OGG1. Our interest in RelA Ser 276 phosphorylation is based on the finding that this post-translational modification modifies NFkB’s association with the positive transcriptional elongation complex, a complex including the epigenetic reader (and histone acetyltransferase) bromodomain 4 (BRD4) . Our more recent work has demonstrated that the BRD4 coactivator plays a major role in global activation of NFkB dependent genes, the IRF-RIG-I cross-talk pathway and interferon response genes. Current questions being examined include the role of the epithelium in controlling the innate inflammatory response using tissue specific inducible Cre-Lox systems, the role of the DNA damage response pathway as an “inside-out” signaling pathway required for “outside-in” signaling from pattern recognition receptors.
2. Systems level studies of the NFkB-BRD4 pathway. Through NHLBI- and NIAID-funded proteomics centers, my center developed an integrated systems-level approach focusing on the NFkB network in airway epithelial cells using RNA-Seq, chromatin immunoprecipitation (ChIP)- Seq, and protein interaction studies. In these studies, we have developed new statistical and informatics tools to interpret and understand the high throughput data. These methods include improvements in inferring gene regulatory networks from ChIP-seq studies, based on signatures of active promoters from ENCODE data bases. We developed methods for statistical inference of error using mixed effects modeling. More recently, we used unbiased proteomic studies of NFkB and CDK9 interactomes as training data for a large scale inference study to identify transcriptional modulators. This latter work informed our understanding that groups of modulators are coupled to different gene expression modes that control distinct biological pathways. Current questions being examined include the BRD4 interactome and how it is affected by innate signaling, and systems level studies of pausing and pause-release using NGS.
3. Role of NFkB-BRD4 in mesenchymal cell-state transition. We have been investigating the mechanism of type II epithelial mesenchymal transition (EMT) in stem-cell like bronchiolar cells. We have observed that type II EMT, mesenchymal transition of primary cells, is mechanistically distinct from the better-studied type III EMT, mesenchymal transition of transformed cells, because distinct gene regulatory networks are activated. In this model, we have implicated the NFkB-BRD4 pathway as a major pathway controlling the core SNAI, ZEB and Twist transcriptional repressors. We have demonstrated in vivo that that persistent activation of the innate pathway induces mesenchymal transition, myofibroblast expansion and fibrosis in an animal model. Several exciting findings have in airway remodeling; this exciting finding provides a mechanistic link for how frequent viral induced airway exacerbations are linked to airway remodeling and disease progression. We have established an active collaboration with SCMM medicinal chemists to identify novel small molecule inhibitors of BRD4. Our current approaches include the clinical advancement of small molecule inhibitors using nanoparticle delivery systems partly funded through an innovation award from Sanofi-Institute Pasteur.
Peer reviewed manuscripts
- Tian B, Yang J, Zhao Y, Ivanciuc T, Sun H, Garofalo RP, Brasier AR. Bromodomain Containing 4 (BRD4) Couples NFkB/RelA With Airway Inflammation And The IRF-RIG-I Amplification Loop In Respiratory Syncytial Virus Infection Journal of Virology. 2017;in press:PMID: 28077651. doi: doi: 10.1128/JVI.00007-17
- Yang J, Tian B, Sun H, Garofalo R, Brasier AR. ZEB1 mediated epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition. Nature Microbiology. 2017;17086 (2017) | DOI: 10.1038/nmicrobiol.2017.86
- Liu Z, Wang P, Chen H, Wold E, Tian B, Brasier AR, Zhou J. Drug Discovery Targeting Bromodomain-Containing Protein 4 (BRD4). Journal of Medical Chemistry. 2017;in press.
- Ijaz T, Jamaluddin M, Zhao Y, Zhang Y, Finnerty CC, Jay J, Herndon D, Tilton R, Brasier AR. Coordinate activities of BRD4 and CDK9 in the transcriptional elongation complex are required for TGFb-induced Nox4 expression and myofibroblast transdifferentiation Cell Death Differ. 2017;8(2)::e2606. doi: 10.1038/cddis.2016.434.
- Zhao Y, Jamaluddin M, Zhang Y, Sun H, Ivanciuc T, Garofalo RP, Brasier AR. Systematic Analysis of Cell-Type Differences in the Epithelial Secretome Reveals Insights into the Pathogenesis of Respiratory Syncytial Virus-Induced Lower Respiratory Tract Infections. Journal of immunology (Baltimore, Md : 1950). 2017;198(8):3345-64. doi: 10.4049/jimmunol.1601291. PubMed PMID: 28258195; PMCID: PMC5380581.
- Hosoki K, Aguilera-Aguirre L, Brasier AR, Kurosky A, Boldogh I, Sur S. Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment. Am J Respir Cell Mol Biol. 2016;54(1):81-90. doi: 10.1165/rcmb.2015-0044OC. PubMed PMID: 26086549; PMCID: PMC4742928.
- Tian B, Zhao Y, Sun H, Zhang Y, Yang J, Brasier AR. BRD4 Mediates NFkB-dependent Epithelial-Mesenchymal Transition and Pulmonary Fibrosis via Transcriptional Elongation. The American Journal of Physiology -Lung Cellular and Molecular Physiology 2016;311(6):L1183-L201. doi: 10.1152/ajplung.00224.2016; PMCID: PMC5206405.
- Zhao Y, Tian B, Sadygov RG, Zhang Y, Brasier AR. Integrative proteomic analysis reveals reprograming tumor necrosis factor signaling in epithelial mesenchymal transition. J Proteomics. 2016;148:126-38. Epub 2016/07/28. doi: 10.1016/j.jprot.2016.07.014. PubMed PMID: 27461979.
- Hosoki K, Boldogh I, Aguilera-Aguirre L, Sun Q, Itazawa T, Hazra T, Brasier AR, Kurosky A, Sur S. Myeloid differentiation protein 2 facilitates pollen- and cat dander-induced innate and allergic airway inflammation. The Journal of allergy and clinical immunology. 2016;137(5):1506-13.e2. Epub 2015/11/21. doi: 10.1016/j.jaci.2015.09.036. PubMed PMID: 26586036; PMCID: PMC4860180.
- Tian B, Widen SG, Yang J, Wood TG, Kudlicki A, Brasier AR. NFkB is a Master Transcription Factor of the Epithelial-Mesenchymal Transition Activating WNT- and TGFb Autocrine Loops through Epigenetic Regulation of Acetylated H3K27 Marks. Nucleic Acids Res. 2016;in press.
- Tian B, Patrikeev I, Ochoa L, Vargas G, Belanger KK, Litvinov J, Boldogh I, Ameredes BT, Motamedi M, Brasier AR. NFkappaB Mediates Mesenchymal Transition, Remodeling and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns. Am J Respir Cell Mol Biol. 2016. Epub 2016/12/03. doi: 10.1165/rcmb.2016-0259OC. PubMed PMID: 27911568.
- Ijaz T, Wakamiya M, Sun H, Recinos A, 3rd, Tilton RG, Brasier AR. Generation and characterization of a novel transgenic mouse harboring conditional nuclear factor-kappa B/RelA knockout alleles. BMC Dev Biol. 2016;16(1):32. doi: 10.1186/s12861-016-0135-8. PubMed PMID: 27662828; PMCID: PMC5034478.
- Fang L, Choudhary S, Tian B, Boldogh I, Yang C, Ivanciuc T, Ma Y, Garofalo RP, Brasier AR. Ataxia Telangiectasia Mutated Kinase Mediates NF-kappaB Serine 276 Phosphorylation and Interferon Expression via the IRF7-RIG-I Amplification Loop in Paramyxovirus Infection. J Virol. 2015;89(5):2628-42. doi: 10.1128/JVI.02458-14. PubMed PMID: 25520509; PMCID: PMC4325710.
- Desai P, Yang J, Tian B, Sun H, Kalita M, Ju H, Paulucci-Holthauzen A, Zhao Y, Brasier AR, Sadygov RG. Mixed-effects model of epithelial-mesenchymal transition reveals rewiring of signaling networks. Cell Signal. 2015;27(7):1413-25. Epub 2015/04/12. doi: 10.1016/j.cellsig.2015.03.024. PubMed PMID: 25862520; PMCID: PMC4437893.
- Li X, Zhu M, Brasier AR, Kudlicki AS. Inferring Genome-Wide Functional Modulatory Network: A Case Study on NF-kappaB/RelA Transcription Factor. Journal of computational biology : a journal of computational molecular cell biology. 2015;22(4):300-12. Epub 2015/04/07. doi: 10.1089/cmb.2014.0299. PubMed PMID: 25844669; PMCID: PMC4394173.
- Tian B, Li X, Kalita M, Widen SG, Yang J, Bhavnani SK, Dang B, Kudlicki A, Sinha M, Kong F, Wood TG, Luxon BA, Brasier AR. Analysis of the TGFbeta-induced program in primary airway epithelial cells shows essential role of NF-kappaB/RelA signaling network in type II epithelial mesenchymal transition. BMC Genomics. 2015;16(1):529. doi: 10.1186/s12864-015-1707-x. PubMed PMID: 26187636; PMCID: PMC4506436.
- Zhou Q, Costinean S, Croce CM, Brasier AR, Merwat S, Larson SA, Basra S, Verne GN. MicroRNA 29 targets nuclear factor-kappaB-repressing factor and Claudin 1 to increase intestinal permeability. Gastroenterology. 2015;148(1):158-69.e8. Epub 2014/10/04. doi: 10.1053/j.gastro.2014.09.037. PubMed PMID: 25277410; PMCID: Pmc4303568.
- Brasier AR, Zhao Y, Wiktorowicz JE, Spratt HM, Nascimento EJ, Cordeiro MT, Soman KV, Ju H, Recinos A, 3rd, Stafford S, Wu Z, Marques ET, Jr., Vasilakis N. Molecular classification of outcomes from dengue virus -3 infections. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2015;64:97-106. Epub 2015/03/03. doi: 10.1016/j.jcv.2015.01.011. PubMed PMID: 25728087; PMCID: Pmc4346782.
- Yang J, Zhao Y, Kalita M, Li X, Jamaluddin M, Tian B, Edeh CB, Wiktorowicz JE, Kudlicki A, Brasier AR. Systematic Determination of Human Cyclin Dependent Kinase (CDK)-9 Interactome Identifies Novel Functions in RNA Splicing Mediated by the DDX5/17 RNA Helicases. Molecular & cellular proteomics : MCP. 2015. Epub 2015/07/26. doi: 10.1074/mcp.M115.049221. PubMed PMID: 26209609; PMCID: Free full text.
- Bhavnani SK, Dang B, Bellala G, Divekar R, Visweswaran S, Brasier AR, Kurosky A. Unlocking proteomic heterogeneity in complex diseases through visual analytics. Proteomics. 2015;15(8):1405-18. Epub 2015/02/17. doi: 10.1002/pmic.201400451. PubMed PMID: 25684269; PMCID: Pmc4471338.
- Hosoki K, Aguilera-Aguirre L, Brasier AR, Kurosky A, Boldogh I, Sur S. Pollen-induced Innate Recruitment of Neutrophils Facilitates Induction of Allergic Sensitization and Airway Inflammation. Am J Respir Cell Mol Biol. 2015. Epub 2015/06/19. doi: 10.1165/rcmb.2015-0044OC. PubMed PMID: 26086549; PMCID: PMC-in process.
- Brasier AR, Zhao Y, Spratt HM, Wiktorowicz JE, Ju H, Wheat LJ, Baden L, Stafford S, Wu Z, Issa N, Caliendo AM, Denning DW, Soman K, Clancy CJ, Nguyen MH, Sugrue MW, Alexander BD, Wingard JR. Improved Detection of Invasive Pulmonary Aspergillosis Arising during Leukemia Treatment Using a Panel of Host Response Proteins and Fungal Antigens. PLoS ONE. 2015;10(11):e0143165. doi: 10.1371/journal.pone.0143165.
- Zhao Y, Valbuena G, Walker DH, Gazi M, Hidalgo M, De Sousa R, Oteo JA, Goez Y, Brasier AR. Endothelial cell proteomic response to Rickettsia conorii infection reveals activation of the Jak-STAT-ISG15 pathway and reprogramming plasma membrane integrin/cadherin signaling. Molecular & Cellular Proteomics. 2015. doi: 10.1074/mcp.M115.054361.
- Aguilera-Aguirre L, Hosoki K, Bacsi A, Radak Z, Sur S, Hegde ML, Tian B, Saavedra-Molina A, Brasier AR, Ba X, Boldogh I. Whole transcriptome analysis reveals a role for OGG1-initiated DNA repair signaling in airway remodeling. Free Radic Biol Med. 2015;89:20-33. doi: 10.1016/j.freeradbiomed.2015.07.007. PubMed PMID: 26187872.
- Aguilera-Aguirre L, Hosoki K, Bacsi A, Radak Z, Wood TG, Widen SG, Sur S, Ameredes BT, Saavedra-Molina A, Brasier AR, Ba X, Boldogh I. Whole transcriptome analysis reveals an 8-oxoguanine DNA glycosylase-1-driven DNA repair-dependent gene expression linked to essential biological processes. Free Radic Biol Med. 2015;81:107-18. doi: 10.1016/j.freeradbiomed.2015.01.004. PubMed PMID: 25614460; PMCID: PMC4359954.
- Ijaz T, Pazdrak K, Kalita M, Konig R, Choudhary S, Tian B, Boldogh I, Brasier AR. † Systems biology approaches to understanding Epithelial Mesenchymal Transition (EMT) in mucosal remodeling and signaling in asthma. World Allergy Organ J. 2014; 7(1):13. doi: 10.1186/1939-4551-7-13. PMID: 24982697. PMC-in process.
- Bhavnani SK, Dang B, Bellala G, Divekar R, Visweswaran S, Brasier AR, Kurosky A Unlocking proteomic heterogeneity in complex diseases through visual analytics. Proteomics. 2015 Apr;15(8):1405-18. doi: 10.1002/pmic.201400451.
- Choudhary S, Boldogh I and Brasier AR†. Inside-Out Signaling Pathways From Nuclear ROS Control Pulmonary Innate Immunity. Journal of Innate Immunity. 2016;8(2):143-55.
- Ijaz T, Tilton RG, Brasier AR†. Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation. J Thorac Dis. 2016;8(8):E746-54. PMCID: PMC4999690. Citations: 1.
- Wiktorowicz JE, Brasier AR. Introduction to Clinical Proteomics. Adv Exp Med Biol. 2016; 919:435-441.
- Zhao Y, Brasier AR. Qualification and Verification of Protein Biomarker Candidates. Adv Exp Med Biol. 2016; 919:493-514.
- Yang J, Tian, B, Brasier AR†. “Targeting chromatin remodeling in inflammation and fibrosis”. In Chromatin Proteins and Transcription Factors as Therapeutic Targets Donev, R., Ed. Advances in Protein Chemistry and Structural Biology. 2017; 107:1-36, Academic Press.
A.R. Brasier (ed.), Heterogeneity in Asthma, Advances in Experimental Medicine and Biology 795, DOI 10.1007/978-1-4614-8603-9_17,© Springer Science+Business Media New York 2014.