A26 INDUCTION OF A CELLULAR MIGRATION PROGRAM THROUGH PAR2 ACTIVATION IN COLONIC EPITHELIAL CELLS
Bibliographic record
Abstract
Inflammatory bowel disease (IBD) treatments are ineffective for many patients and where they are helpful, lose their efficacy over time. However, the mechanisms that determine mucosal healing, the key goal of therapy, are complex and incompletely understood. The inflammatory environment is characterized by the presence of several serine proteases that signal through the protease-activated receptors (PARs). PAR2 is ubiquitously expressed in the epithelial cells of the intestinal mucosa, and our previous studies suggest that PAR2 activation serves a protective role consistent with host defence and repair. While our preliminary findings indicate that activation of PAR2 enhances wound healing, we do not know the cellular mechanisms that underlie this response. We hypothesize that activation of PAR2 induces a cellular migration program in intestinal epithelial cells that enhances mucosal healing. T84 colonic epithelial cells were grown to confluence before circular wounds were made by a pipette tip attached to the end of an aspirator. Wounded monolayers were treated with PAR2 activating peptide 2-furoyl-LIGRLO (2fLI, 5 µM) or the control reverse-sequence peptide 2-furoyl-OLRGIL (2fO, 5 µM) and live cell microscopy was utilized to record wound healing over a 24 hr period. A 2fLI concentration-response (0.1 µM – 10 µM) was first performed. A cytokine cocktail consisting of IFNγ (10 ng/mL), TNFα (10 ng/mL), and IL-1β (10 ng/mL) was applied to wounded monolayers with and without 2fLI (5 µM) treatment and wound healing was then assessed. PAR2 activation and cytokine functionality were validated by immunoblot of targets of canonical signaling pathways. PAR2 activation by 2fLI promoted wound healing in a concentration-dependent manner (0.1 µM – 10 µM) compared to 2fO controls at the 24 hr timepoint. 5 µM 2fLI caused the maximal response at the 24 hr timepoint (p<0.001). Treatment with a cytokine cocktail also promoted a significantly increased wound healing response compared to the untreated controls (p<0.05). Co-stimulation with 2fLI and the cytokine cocktail resulted in an additive wound healing response at the 24 hr timepoint and was significantly greater than individual treatments (p<0.001). PAR2 activation resulted in the activation of the ERK/MAPK pathway while the cytokine cocktail activated both the JAK and ERK/MAPK pathways. The data suggest that both PAR2 activation and cytokine treatment promote a wound healing program in vitro. An additive wound healing effect occurs upon PAR2 activation in the presence of pro-inflammatory cytokines, which suggest that the inflammatory milieu is integral to initiate a proper wound healing response. CCC, CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".