P-202 Role of NOD1 and NOD2 in Colitis-Associated Cancer (CAC)
Bibliographic record
Abstract
Chronic inflammation is intimately linked to tumorigenesis as illustrated in IBD patients who are significantly more susceptible for later development of colon cancer. However, the mechanisms underlying colitis-associated carcinogenesis (CAC) remain poorly defined. A hallmark of IBD involves the disruption of the intestinal epithelium. Intestinal epithelial cells (IECs), the main constituents of the intestinal barrier, are constantly regenerated to maintain the integrity of the epithelium. Accordingly, the pathology of IBD and susceptibility to CAC is believed to stem from a disruption of epithelial homeostasis. Several microbial sensors have evolved to help maintain this balance, including the Toll-like (TLR) and Nod-like (NLR) families of innate immune receptors. The NLR genes NOD1/CARD4 and NOD2/CARD15 are particularly relevant as they are associated with increased susceptibility to IBD and cancer. Nonetheless, while NOD1 and NOD2 are both expressed in IECs, it remains largely unknown how NLR signaling in enterocytes contributes to the maintenance of the intestinal epithelial barrier and regulation of intestinal inflammation. Our laboratory has recently developed a mouse model with IEC-specific deletion of NOD1 and NOD2 to investigate the detailed contribution of NOD signaling in colitis and colorectal cancer. IEC-specific NOD1- and NOD2-dificient animals were generated by crossing NOD1- and NOD2-loxP flanked mice to transgenic mice expressing the Cre recombinase under the control of the IEC-specific promoter, villin-1. Using these unique cell specific knockout mice, we have established mouse models of chemically induced colitis and CAC. Our preliminary results suggest that NOD1 expression in IECs exacerbates inflammation in the DSS model of acute colitis. NOD1IEC-KO mice experienced reduced severity of DSS-induced colitis characterized by less weight loss when compared to their NOD1IEC-WT littermates. Similarly, “whole-body” NOD1 expression did not protect mice from colitis. Moreover, NOD1-deficient mice exposed to the AOM/DSS model had less dysplasia and fewer invasive tumors compared to WT mice. While a small cohort was used, preliminary results indicate that NOD1IEC-KO mice may also be protected from CAC development with a trend towards fewer tumors and fewer large tumors. Taken together, our preliminary work illustrates a role for IEC-specific expression of NOD1 in intestinal inflammation and CAC.
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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 | 0.002 |
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".