A20 INTESTINAL SMOOTH MUSCLE AND FIBROSTENOSIS: TARGETING NR4A1 TO MODULATE PROLIFERATIVE SIGNALLING
Bibliographic record
Abstract
Abstract Background Fibrostenotic Crohn’s Disease (CD), presenting with intestinal fibrosis and stricture formation, has a substantial impact on patient quality of life. Given our poor understanding of its etiology, we lack viable preventative and therapeutic methods. While much focus has been on the fibrotic component, recent studies have implicated the role of intestinal smooth muscle cell (SMC) hyperplasia/hypertrophy in stricture formation. These data suggest targeting SMC proliferation may provide benefit for fibrostenotic CD patients. NR4A1 (nuclear receptor subfamily 4 group A member 1) is an orphan nuclear receptor that has shown to regulate inflammation in experimental models of colitis and dampen SMC proliferation and fibrotic signalling in intestinal and non-intestinal systems. Thus, we sought to characterize the role of NR4A1 in regulating proliferative signalling in intestinal SMCs to determine whether it could be a therapeutic target for fibrostenotic CD. Aims To determine how NR4A1 regulates intestinal SMC proliferative responses to mitogenic signalling. Methods Primary intestinal SMCs were isolated from the colonic tissue of Nr4a1+/+ and Nr4a1-/- mice. A commercially available human colonic SMC line was also used. EdU incorporation assays were used to quantify the relative proliferation of Nr4a1+/+ and Nr4a1-/- SMCs in their basal or stimulated state (with platelet-derived growth factor (PDGF)-BB). In addition, NR4A1 was activated using selective agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP). Differences in PDGF-BB-induced intracellular signalling was determined using western blotting of phosphorylated proteins after stimulation. Quantification of PDGF receptor transcript expression in Nr4a1+/+ and Nr4a1-/- SMCs was done using qPCR. Finally, immunofluorescence was used to determine the localization of NR4A1 when stimulated with Csn-B, 6-MP, and/or PDGF-BB. Results The proliferation assays showed that Nr4a1-/- SMCs exhibit greater proliferation at baseline and when stimulated with PDGF-BB, compared to Nr4a1+/+ SMCs. However, this was not associated with any differences in the intracellular signalling directly downstream of PDGF receptor activation. Specifically, there were no differences in the intensity and temporal characteristics of Akt- and Erk1/2-phosphorylation between Nr4a1+/+ and Nr4a1-/- SMCs. Interestingly, Nr4a1-/- SMCs had less expression of Pdgfrb, the gene encoding PDGF receptor beta, when compared to Nr4a1+/+ SMCs. However, no changes in receptor expression were observed when SMCs were stimulated with Csn-B and 6-MP. Conclusions We show that NR4A1 regulates basal and PDGF-BB-induced SMC proliferation, without directly altering the intracellular signalling cascades induced by receptor activation. Our data supports NR4A1 as a target to control the aberrant SMC proliferation that contributes to fibrostenosis. Funding Agencies CIHR
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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".