A265 INVOLVEMENT OF LRP6 IN INTESTINAL HOMEOSTASIS AND INFLAMMATION
Bibliographic record
Abstract
Self-renewal of the intestinal epithelium is tightly regulated by interacting intracellular signaling pathways, which control stem cell proliferation and differentiation. In particular, Wnt/b-catenin signalling controls crypt cell proliferation and survival and is required for maintenance of intestinal stem cells. Additionally, maturation of Paneth cells in the intestine also depends on this pathway. Wnt signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3β activity, resulting in increased nuclear β-catenin. Recently, LRP6 was identified as a new candidate gene in ileal Crohn’s Disease (Koslowski, PLoS Genet 2012). In the present study we would like to explored whether LRP6 is required for the maintenance of intestinal homeostasis and barrier function. Using the Cre/loxP system, mice with an intestinal epithelial cell-specific deletion of LRP6 (LRP6IEC-KO mice) were generated. Tissue architecture was visualized with hematoxylin-eosin staining and Paneth cells by lysozyme staining. Intestinal permeability was evaluated by dextran-FITC method. Crypts were isolated from control and mutant mice and organoid cultures were established as an ex vivo model of epithelial regeneration. The sensitivity of mice to inflammation was evaluated by giving 2% DSS to mice for 7 days. Mice were scored based on a scale of 0 to 4 for stool consistency, rectal bleeding, colon hardness and blood loss, and a cumulative disease activity index (DAI) was calculated. Loss of LRP6 expression was validated in LRP6IEC-KO mice compared to control mice. At 4 weeks of age, no difference in body weight of LRP6IEC-KO mice was noticed in comparison to control mice. Histological analyses indicate that the architecture of the small and large intestine was apparently not altered. Surprisingly, the number of proliferative cells remained unchanged in LRP6IEC-KO mice and no difference in Paneth cell number was seen. However, intestinal permeability was markedly increased in 3-month-old LRP6IEC-KO mice compared to control littermates. Furthermore, deletion of LRP6 clearly impaired organoid development as determined by measurement of both organoid growth and budding. Finally, LRP6IECKO mice were much more sensitive to DSS treatment in comparison to control littermates. These results suggest that LRP6 regulates IEC-mediated mucosal homeostatic and inflammatory responses. CIHRCRCHUS
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".