Intestinal tight junction <i>CLDN2</i> gene is a direct target of the vitamin D receptor
Bibliographic record
Abstract
The breakdown of intestinal barrier is a common manifestation of GI disorders. Claudin‐2 is a tight junction protein that mediates paracellular water transport in leaky epithelium. Recent evidence suggests that vitamin D and vitamin D receptor (VDR) may regulate functions of tight junction proteins. However, it is unknown how Claudin‐2 is regulated by VDR signaling in normal and inflamed intestine. Using whole body VDR ‐/‐ mice, intestinal epithelial VDR conditional knockout (VDR ΔIEC ) mice, human samples, and cultured human intestinal epithelial cells (IEC), we performed a series of molecular and biochemical experiments in vivo and in vitro . We provide evidence that the CLDN2 gene is a direct target of the transcription factor VDR. VDR‐inducing Claudin‐2 promoter activity required the Cdx binding site on the promoter of the CLDN2 gene. We further identify a functional vitamin D response element in the Claudin‐2 promoter. In vivo , VDR deletion in intestinal epithelial cells (IEC) led to decreased Claudin‐2 at both mRNA and protein levels. Functionally, we found a robust increase of Claudin‐2 in inflammatory IECs which lacked VDR regulation and allowed the inflammatory cytokines to take over. Furthermore, in inflamed intestine of ulcerative colitis patients, VDR expression is low and Claudin‐2 is enhanced. A lack of intestinal VDR regulation leads to dysfunction of Claudin‐2 in inflammatory responses. This study reveals a complex role and novel mechanism for intestinal VDR by regulation of epithelial barriers and inflammation.
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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".