Optimizing external advisory committee meetings of Clinical and Translational Science Awards through focused pre-review.

External advisory committees (EACs) are critical peer-review meetings that drive improvement at Clinical and Translational Science Award Program Hubs. Despite their ubiquity, evaluations of EAC optimization and effective implementation remain scarce. We present a two-tiered approach to optimizing EAC meetings through (1) in-depth, topically focused "pre-review" meetings comprised of external topic experts and at least one standing "full-board" EAC member, followed by (2) a traditional "full-board" EAC meeting.

NF-κB/RelA signaling in secretoglobin progenitors mediates plasticity and MMP-induced barrier disruption in house dust mite-induced allergic asthma.

The mechanisms how aeroallergens induce sensitization are incompletely understood. The house dust mite (HDM) (Der p) is a ubiquitous aeroallergen that represents a major cause of allergic rhinitis and asthma. Herein, we tested whether HDM-induced aeroallergen exposure sensitivity is caused by the innate-immune response in small airway epithelial cells.

Cooperative interaction of interferon regulatory factor -1 and bromodomain-containing protein 4 on RNA polymerase activation for intrinsic innate immunity.

Introduction: The human orthopneumovirus, Respiratory Syncytial Virus (RSV), is the causative agent of severe lower respiratory tract infections (LRTI) and exacerbations of chronic lung diseases. In immune competent hosts, RSV productively infects highly differentiated epithelial cells, where it elicits robust anti-viral, cytokine and remodeling programs. By contrast, basal cells are relatively resistant to RSV infection, in part, because of constitutive expression of an intrinsic innate immune response (IIR) consisting of a subgroup of interferon (IFN) responsive genes.

Developing a Translational Team Training Program using the Wisconsin Interventions in Team Science Framework.

The Clinical and Translational Science Awards (CTSA) Program supports a national network of medical research institutions working to improve the translational process. High-performing translational teams (TTs) are critical for advancing evidence-based approaches that improve human health. When focused on content-appropriate knowledge, skills, and attitudes, targeted training results in the substantial internalization of training content, producing new skills that can be applied to improve team outputs, outcomes, and benefits.

A leadership model supporting maturation of high-performance translational teams.

Despite understanding its impact on organizational effectiveness, practical guidance on how to train translational team (TT) leaders is lacking. Previously, we developed an evolutionary learning model of TT maturation consisting of three goal-directed phases: (1). team assembly (); (2).

Substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) reprograms mucosal adaptations to chronic airway injury.

Recent advances have uncovered the non-random distribution of 7, 8-dihydro-8-oxoguanine (8-oxoGua) induced by reactive oxygen species, which is believed to have epigenetic effects. Its cognate repair protein, 8-oxoguanine DNA glycosylase 1 (OGG1), reads oxidative substrates and participates in transcriptional initiation. When redox signaling is activated in small airway epithelial cells, the DNA repair function of OGG1 is repurposed to transmit acute inflammatory signals accompanied by cell state transitions and modification of the extracellular matrix.

Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1.

Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges.

RSV replication modifies the XBP1s binding complex on the IRF1 upstream enhancer to potentiate the mucosal anti-viral response.

Introduction: The unfolded protein response (UPR) has emerged as an important signaling pathway mediating anti-viral defenses to Respiratory Syncytial Virus (RSV) infection. Earlier we found that RSV replication predominantly activates the evolutionarily conserved Inositol Requiring Enzyme 1α (IRE1α)-X-Box Binding Protein 1 spliced (XBP1s) arm of the Unfolded Protein Response (UPR) producing inflammation, metabolic adaptation and cellular plasticity, yet the mechanisms how the UPR potentiates inflammation are not well understood.

Methods: To understand this process better, we examined the genomic response integrating RNA-seq and Cleavage Under Targets and Release Using Nuclease (CUT&RUN) analyses.

Innate Immunity, Epithelial Plasticity, and Remodeling in Asthma.

Innate immune responses (IIR) of the epithelium play a critical role in the initiation and progression of asthma. The core of the IIR is an intracellular signaling pathway activated by pattern recognition receptors (PRRs) to limit the spread of infectious organisms. This chapter will focus on the epithelium as the major innate sentinel cell and its role in acute exacerbations (AEs).

Bromodomain-containing Protein 4 regulates innate inflammation via modulation of alternative splicing.

Introduction: Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In the context of airway viral infection, BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream epithelial plasticity. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not well understood.

Temporal development of high-performance translational teams.

Successful translation involves the coupled application of knowledgegenerating research with product development to advance a device, drug, diagnostic, or evidence-based intervention for clinical adoption to improve human health. Critical to the success of the CTSA consortium, translation can be more effectively accomplished by training approaches that focus on improving team-emergent knowledge skills and attitudes (KSAs) linked to performance. We earlier identified 15 specific evidence-informed, team-emergent competencies that facilitate translational team (TT) performance.

Win-win interactions: Results and implications of a user needs assessment of clinical and translational scientists.

Introduction: This study describes a needs assessment of clinical and translational research (CTR) scientists at a large, distributed, School of Medicine within a public university and affiliated clinics.

Method: We performed an Exploratory Conversion Mixed-Methods analysis using a quantitative survey and qualitative interviews with CTR scientists across the training continuum, from early-career scholars, mid-career mentors, and senior administrators at the University of Wisconsin and Marshfield Clinics. Qualitative findings were confirmed using epistemic network analysis (ENA).

Competencies supporting high-performance translational teams: A review of the SciTS evidence base.

A translational team (TT) is a specific type of interdisciplinary team that seeks to improve human health. Because high-performing TTs are critical to accomplishing CTSA goals, a greater understanding of how to promote TT performance is needed. Previous work by a CTSA Workgroup formulated a taxonomy of 5 interrelated team-emergent competency "domains" for successful translation: 1).

Genomic targets of the IRE1-XBP1s pathway in mediating metabolic adaptation in epithelial plasticity.

Epithelial mesenchymal plasticity (EMP) is a complex cellular reprogramming event that plays a major role in tissue homeostasis. Recently we observed the unfolded protein response (UPR) triggers EMP through the inositol-requiring protein 1 (IRE1α)-X-box-binding protein 1 spliced (XBP1s) axis, enhancing glucose shunting to protein N glycosylation. To better understand the genomic targets of XBP1s, we identified its genomic targets using Cleavage Under Targets and Release Using Nuclease (CUT&RUN) of a FLAG-epitope tagged XBP1s in RSV infection.

Bromodomain-containing Protein 4 Regulates Innate Inflammation in Airway Epithelial Cells via Modulation of Alternative Splicing.

Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In airway viral infection, non-toxic BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream remodeling. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not as well understood.

Special Issue "Next-Generation Technologies to Understand Mechanisms of Virus Infections".

RNA viruses are responsible for substantial morbidity and health burden [...

8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury.

Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated.

The IRE1α-XBP1s Arm of the Unfolded Protein Response Activates N-Glycosylation to Remodel the Subepithelial Basement Membrane in Paramyxovirus Infection.

Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded protein response (UPR), which is a pathway controlling protein glycosylation and secretion of the extracellular matrix (ECM). Because the presence of matrix metalloproteinases and matricellular growth factors (TGF) is associated with severe LRTI, we studied the effect of RSV on ECM remodeling and found that RSV enhances the deposition of fibronectin-rich ECM by small airway epithelial cells in a manner highly dependent on the inositol requiring kinase (IRE1α)-XBP1 arm of the UPR.

RELA∙8-Oxoguanine DNA Glycosylase1 Is an Epigenetic Regulatory Complex Coordinating the Hexosamine Biosynthetic Pathway in RSV Infection.

Respiratory syncytial virus (RSV), or human orthopneumovirus, is a negative-sense RNA virus that is the causative agent of severe lower respiratory tract infections in children and is associated with exacerbations of adult lung disease. The mechanisms how severe and/or repetitive virus infections cause declines in pulmonary capacity are not fully understood. We have recently discovered that viral replication triggers epithelial plasticity and metabolic reprogramming involving the hexosamine biosynthetic pathway (HBP).

Selective Inhibition of Bromodomain-Containing Protein 4 Reduces Myofibroblast Transdifferentiation and Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular matrix (ECM) production. We have recently shown that bromodomain-containing protein 4 (BRD4), an epigenetic regulator that forms a scaffold for nuclear activators and transcription factors, is essential for TGFβ-induced myofibroblast transdifferentiation.

Segmental Bronchial Allergen Challenge Elicits Distinct Metabolic Phenotypes in Allergic Asthma.

Asthma is a complex syndrome associated with episodic decompensations provoked by aeroallergen exposures. The underlying pathophysiological states driving exacerbations are latent in the resting state and do not adequately inform biomarker-driven therapy. A better understanding of the pathophysiological pathways driving allergic exacerbations is needed.

Airway fibrin formation cascade in allergic asthma exacerbation: implications for inflammation and remodeling.

Background: Airway remodeling in patients with asthma, which leads to a decline in pulmonary function, is likely the result of repeated exacerbations often provoked by aeroallergen exposures. Aeroallegen exposure triggers a stereotypic response orchestrated by growth factor cytokines and other protein mediators. This results in a late-phase allergic reaction characterized by vascular permeability, recruitment of activated leukocytes, and activation of structural cells of the airway.