A7 PI3KP110δ DRIVES INTESTINAL FIBROSIS IN SHIP DEFICIENT MICE
Bibliographic record
Abstract
Crohn’s disease (CD) is an immune-mediated disease characterized by inflammation along the gastrointestinal tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Despite dramatic improvements in reducing intestinal inflammation in people with CD, some still develop fibrosis and there are no treatments that target intestinal fibrosis directly. Our laboratory has reported that mice deficient in the Src homology 2 domain-containing inositolphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation with arginase-dependent fibrosis. We have also reported that high arginase activity in SHIP-/- cells is dependent on the p110δ catalytic subunit of class IA phosphatidylinositol 3-kinase (PI3K). Based on this, we hypothesize that SHIP-/- mice develop CD-like intestinal fibrosis due to increased PI3Kp110δ activity. Aim 1: To determine whether genetic inactivation of PI3Kp110δ activity prevents the development of ileal fibrosis in SHIP-/- mice Aim 2: To determine whether pharmacological inhibition of PI3Kp110δ activity can block or reverse ileal fibrosis in SHIP-/- mice SHIP-/- mice were crossed with mice deficient in PI3Kp110δ activity (PI3Kp110δDA/DA) to generate wild type, SHIP-/-, PI3Kp110δDA/DA, and SHIP-/-PI3Kp110δDA/DA mice. Mice were assessed for fibrosis and compared at 4, 8, and 12 weeks of age. SHIP-/- mice (8-week-old) were treated with the PI3Kp110δ isoform-specific inhibitor, IC87114 (or vehicle), for two weeks. Ileal fibrosis was assessed in 8-week-old SHIP-/- mice and compared to mice treated with inhibitor or vehicle. Measurements of ileal fibrosis include muscle thickening, accumulation of vimentin+ mesenchymal cells, collagen accumulation by Masson’s trichrome staining and Sircol assay, arginase activity, and TGFβ, IL-4, and IL-13. SHIP-/-PI3Kp110δDA/DA mice have less ileal fibrosis than their SHIP-/- littermates including reduced muscle thickening, vimentin+ mesenchymal cells, collagen accumulation, arginase activity, TGFβ, IL-4, and IL-13. Pharmacological inhibition of PI3Kp110δ activity in SHIP-/- mice also reduced the above parameters. Intriguingly, PI3Kp110δ deficiency or inhibition reduced ileal inflammation in SHIP-/- mice including immune cell infiltration and IL-1β production, suggesting that PI3Kp110δ and/or fibrosis, itself, may contribute to inflammation. PI3Kp110δ activity drives ileal fibrosis in SHIP-/- mice. Moreover, targeting PI3Kp110δ activity effectively reverses SHIP-/- ileal fibrosis. Importantly, people with CD have reduced SHIP activity and so fibrosis, in people with CD, may be amenable to treatment by inhibiting PI3Kp110δ activity. Idelalisib, a PI3Kp110δ inhibitor, is already licensed for use in people with certain leukemias and lymphomas, so may be rapidly translatable into effective therapy for intestinal fibrosis in people with CD. CCC, CIHR
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.007 | 0.003 |
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".