A59 EXPLORING THE ROLE OF ARID1A IN COLONIC HOMEOSTASIS AND REGENERATION
Bibliographic record
Abstract
Abstract Background Recent advances in cancer genome analysis have revealed frequently mutated epigenetic regulators as a novel feature in cancer development. Within this context, the Arid1a (AT-rich interactive domain-containing protein 1A) gene, a subunit of the BAF chromatin remodeling complex, has emerged as a frequently mutated gene in many cancers. Additionally, repeated colonic injury caused by diseases such as inflammatory bowel disease (IBD), is also a major risk factor leading to colorectal cancer. Therefore, understanding the connection between colonic epigenetic regulation and its role in response to injury is particularly important for understanding the pathobiology of colorectal cancer. Aims Aim 1: Exploring the role of Arid1a during colonic homeostasis. Mouse model with Arid1a conditionally knocked out in the colon will be analysed at different time points to test whether Arid1a is required during colonic homeostasis. Aim 2: Determining the role of Arid1a during colonic injury and regeneration. Mice will be exposed to a known colitis model to induce colonic injury. Arid1a will be deleted after injury to find out its role during regeneration and recovery from the injury. Methods To examine the effect of Arid1a loss on colonic homeostasis, mice between 6-10 weeks old were injected with 2mg/20g tamoxifen for three days to induce Arid1a knockout using the VilCreERT2; Arid1afl/fl mousseline. Mice were then euthanised using CO2 chamber and analysed 10 days, 3 weeks, and 8 weeks post Arid1a deletion. Histological analysis was performed to examine morphological changes in the colon. To examine the effect of Arid1a on injury caused by colitis, mice were treated with dextran sulfate sodium (DSS) to cause colitis-like injury. Then, Arid1a is deleted by injecting 2mg/20g tamoxifen. Changes in histology and specific cell types will be examined both in the short- and long-term. Results To test whether Arid1a loss alone causes morphological changes in the colon, I compared the crypt lengths between VilCreERT2; Arid1afl/fl mutant mice with their littermate controls and saw that there was no difference in both morphology and length of the crypts. My results show that Arid1a loss in the colon after injury resulted in impaired regeneration characterized by the prolonged loss of goblet cells and cryptal structure in the distal colon. In the long term, Arid1a loss before or after DSS treatment both lead to tumor formation, suggesting that Arid1a is required for colonic regeneration and repair while suppressing tumorigenesis. Conclusions Based on my results, I conclude that Arid1a deletion alone does not cause significant morphological changes in the colon, but this loss affects colonic regeneration and recovery compared to colons with Arid1a intact. In the long term, the dysregulated colonic regeneration may lead to tumorigenesis. Funding Agencies University of Toronto Department of Molecular Genetics
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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) | 0.005 | 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".