A168 KAISO-INDUCED INTESTINAL INFLAMMATION IS ACCOMPANIED BY FAULTY CELL ADHESION AND ABERRANT INTESTINAL REPAIR.
Bibliographic record
Abstract
Kaiso is a member of the POZ-ZF family of transcription factors that play key roles in vertebrate development and disease. We previously reported that intestinal-specific overexpression of Kaiso (KaisoTg ) potentiates Wnt-induced colon cancer and results in chronic inflammation in 1-year old mice. Notably, the intestines of KaisoTg mice exhibit phenotypes reminiscent of human IBD, including leukocyte infiltration, expanded crypts, and blunted villi. However the mechanism underlying Kaiso-induced inflammation was unknown. In this work, we seek to identify the factors/mechanisms predisposing Kaiso transgenic mice to subsequent intestinal inflammation. To assess morphological differences relative to non-transgenic (nonTg) mice, histological comparisons were performed using two independent KaisoTg mouse lines at 8-months of age. Flow cytometry was performed to ascertain differences in immune cell populations. We also performed myeloperoxidase (MPO) activity assays to assess neutrophil activity in KaisoTg mice. Immunohistochemistry (IHC) of cell adhesion proteins was used to determine differences in subcellular location, and western blot was used to quantify differences in their expression. IHC of Ki67 and western blot of Cyclin D1 were used to compare differences in proliferation. To assay in vivo collective cell migration, mice were given a single injection of BrdU and sacrificed 24- and 48-hours post injection. The distance migrated of BrdU-retaining cells was then quantified. In this work, we show that Kaiso overexpression elicits a neutrophil-specific inflammatory response, as indicated by increased MPO activity, elevated mRNA expression of the neutrophil chemokine, MIP-2, and formation of crypt abscesses. To identify the factor(s) predisposing KaisoTg mice to subsequent inflammatory disease, subclinical (12-week old) mice were examined prior to the onset of inflammation. Notably, E-cadherin localization and expression were reduced in subclinical KaisoTg mice, thus weakening the intestinal barrier and predisposing the mice to subsequent inflammation. Subclinical KaisoTg mice also displayed abnormal intestinal renewal mechanisms, such as delayed proliferation and accelerated cell migration. Together, these findings demonstrate that a weakened intestinal barrier and irregular intestinal renewal mechanisms may play a role in the development of subsequent intestinal inflammation caused by Kaiso overexpression. Importantly, our findings may hold clinical significance, since Kaiso expression is elevated in colon cancer and some cases of Crohn’s disease. CIHRNSERC
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".