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Strategic Planning and Working Groups

Held the first Wednesday of every month

 

 

December 2015 SCMM retreat- Systems Biology initiative

  • SCMM Faculty

January 6, 2016

  • Allan Brasier, MD and Panel | SCMM Synthesis

February 3, 2016

  • Panel Discussion | SCMM Data Management

September 7, 2016

  • Allan Brasier, MD | Results of the SCMM center review and next steps for the center

Featured Faculty Seminars

May 4, 2016

  • Eric J. Wagner, PhD | Alternative Polyadenylation: an Emerging Engine Driving Transcriptomic Diversity in Human Disease

June 1, 2016

  • Jared K. Burks. PhD | The Technical Application of Mass Cytometry to Biological Experimentation

November 2, 2016

  • Yingxin Zhao, PhD | Epithelial mesenchymal transition regulates N-glycosylation of extracellular matrix proteins via XBP1 and hexosamine biosynthesis pathway

December 7, 2016

  • Bill Russell, PhD | Biomolecular Resource Facility Past, Present, and Future.

February 2017

  • Andrzej S. Kudlicki. PhD | Histone modifications in Epithelial Mesenchymal Transition

April 4, 2017

  • Bing Tian, PhD | Role of Bromodomain-Containing Protein 4 (BRD4) in innate inflammation-induced airway remodeling

May 3, 2017

  • Istvan Boldogh, DM&B, PhD | 8-Oxoguananine DNA glycosylase1: Beyond Repair of Oxidatively Modified Base Lesion 8-oxoguan

Collaborative working groups (WGs).

Guided by strategic plans developed within SCMM faculty research retreats, we have conducted a staged development of our capacity to conduct systematic studies of translationally relevant questions in chronic airway disease. Chronic airway disease was selected as a theme because 300 million adults and children suffer from asthma, representing a major public health problem worldwide. A steady increase in asthma prevalence has been observed over the last decade; this disease disproportionately affects the pediatric population; children have required increased emergency room visits and hospitalizations. In infants, respiratory syncytial virus (RSV) infections are the leading cause of epidemic respiratory tract infections, producing 120 K hospitalizations in the US annually. In adults, allergen-induced (atopic) asthma accounts for 500 K hospitalizations yearly in the US, at an estimated annual economic cost of $19.7 billion.

Asthma is driven by complex multicellular interactions between the innate immune response of the host to environmental factors. This disease changes the airway mucosa, dysregulates the innate immune response, changes adaptive immunity, produces hyper-reactivity to allergens and causes permanent remodeling/fibrosis. Remodeling is a process that produces a structural change of the airway involving de-differentiation of epithelial cells, disrupting its barrier function, causing mucus hyper-production, and subepithelial fibrosis.

To attack this problem, have formed interdisciplinary WGs that meet regularly to plan experiments and advance their programs. We have organized into three active WGs that meet every two weeks to develop novel integrated biological and informatics approaches taking advantage of our strength in proteomics and bioinformatics. The WGs, their membership, and accomplishments include:

WG1: Epigenetic regulation of the mesenchymal transition

Participating members: Drs. Brasier, Kudlicki, Tian, Widen, Wood, Yang, Zhao.

Purpose:

The goal of this WG is to understand how mesenchymal transition is induced and maintained in primary human airway epithelial cells. A standardized model of mesenchymal transition of primary human epithelial cells was developed and interrogated by RNA-Seq and proteomics studies. Over 3K genes and 4K proteins were identified as being affected by the transition. Bioinformatic analyses of these genes mapping to ENCODE ChIP-seq studies identified three clusters of 40 transcription factors that control this transition. Perturbations of the NFkB signaling pathway has shown that NFB is a key regulator of the EMT and observed that the EMT rewires the innate signaling pathway inducing a distinct genomic response.

References:

  1. 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
  2. Yang J, Tian B, Brasier AR. Targeting Chromatin Remodeling in Inflammation and Fibrosis. In: Donev R, editor. Advances in protein chemistry and structural biology: Elsevier; 2017.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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 Organization Journal. 2014;7(1):13; PMCID: PMC4068075.
  8. Kalita M, Tian B, Gao B, Choudhary S, Wood TG, Carmical JR, Boldogh I, Mitra S, Minna JD, Brasier AR. Systems Approaches to Modeling Chronic Mucosal Inflammation. BioMed Research International. 2013;2013:505864. doi: 10.1155/2013/505864. PubMed PMID: PMC3818818.

WG2: In vivo models of inflammation- induced remodeling.

Participating members: SCMM: Drs. Boldogh, Tian, Ameredes, Calhoun; Partnerships: Center for Biomedical Engineering (M. Motamedi, G. Vargas, I Patrikeev) and designated as a Collaborative Research Team of the NIEHS Center in Environmental Toxicology (K Elferink, Director).

Purpose: No animal models of inflammation-associated remodeling currently exist, although the phenomenon is observed in patients with disease. The purpose of this WG is to establish validated animal models of inflammation-induced remodeling and relate these to severe asthma and COPD in humans. This group has successfully established an exciting model of repetitive innate inflammation-induced airway fibrosis has been established with the hallmarks of epithelial injury and reprogramming. This work has demonstrated innate signaling produces formation of mesenchymal transition in vivo, and the essential role of NFB-BRD4 pathway in mediating this effect.

Publications:

  1. 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
  2. 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.
  3. 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.

WG3: Signaling in Airway Inflammation

Participating members: Drs. Brasier, Garofalo, Boldogh, Casola, Sur, Tian.

Purpose: The purpose of this WG is to understand the role the mucosa plays in facilitating viral and allergen-induced airway inflammation. This WG is supported by an NIAID funded P01 comprised of 4 synergistic, inter-related projects led by SCMM faculty investigating the overall hypothesis that ROS production by the respiratory mucosa activates the innate immune response (IIR), producing airway inflammation. Over 60 multiauthored papers have been published by this program, including 2 patents. Important conceptual advances made during the reporting period include:

These studies are the first to demonstrate that the innate immune response is controlled at the translational elongation step, identifying new to modify airway inflammation.

These studies demonstrated that RSV induces degradation of the master antioxidant transcription factor Nrf2. This project is the first to implicate disruption of the antioxidants in severity of RSV disease. This group is investigating whether Nrf2 polymorphisms are associated with disease severity in children, and evaluating whether Nrf2 mimetics can be used for therapies of severe bronchiolitis.

This group has shown that ROS stress induced by ragweed pollen exposure induces the DNA damage repair product 8-oxoG, which complexes with OGG1, turning it into a guanine nucleotide exchange factor (GEF) controlling small GTPases (Ras, Rac, Rho) to activate inflammation via NFkB. These studies were the first to describe a mechanism linking oxidative DNA damage with acute mucosal inflammation published in Journal of Clinical Investigation.