ING-006 Modulation of GPR40 and GPR84: The Bright/Dark Side Targets in IPF Pathogenesis
Bibliographic record
Abstract
Abstract RATIONALE: ING-006, a dual GPR40 agonist/GPR84 antagonist, plays a key role in genes involved in IPF initiation and progression to fibrosis. The main objectives of this study were 1) to evaluate the gene expression of GPR40 and GPR84 in IPF patients, in the bleomycin-model and in cells involved in fibrosis as well as to correlate the receptor expression with genes involved in fibrosis, and 2) to evaluate the antifibrotic activity of ING-006 on fibroblasts and lung fragments from IPF patients. METHODS: Expression of GPR40 and GPR84 was analysed in a cohort of 213 individuals (91 healthy, 122 IPF patients) from the GEO database (#GSE47460), using DLCO and FVC stratification. GPR40 and GPR84 expression was also measured in a bleomycin model, as well as in activated macrophages, fibroblasts, and epithelial cells treated under fibrotic conditions (IFNγ + LPS, or TGFβ1). The antifibrotic activity of ING-006 was measured in IPF fibroblasts and lung fragments cultured on chorioallantoic membranes (CAM).RESULTS: Under normal conditions, macrophages show high GPR40 and low GPR84 gene expression, however under fibrotic conditions, GPR84 is highly expressed (≥200-fold) while GPR40 is significantly decreased (2-fold). Under fibrotic conditions, GPR84 (expressed in fibroblast) is increased (5-10-fold), while GPR40 (expressed in epithelial cells) is significantly decreased (2-4-fold). Modulation of the expression of both receptors (↓GPR40 and ↑GPR84) is observed in the bleomycin-induced lung fibrosis as well as in IPF patients which also correlates with the %DLCO and the predicted FVC progression/severity of the disease. Additionally, a significant correlation between GPR40 (negative), GPR84 (positive), and remodelling enzyme (MMP1 and MMP7) and PTPRC (CD45), IL-6, CCL2 (MCP-1) is observed in IPF patients while only GPR40 (negative correlation) seems to be associated with genes involved in IPF initiation (DSP, MUC5B and MUC1). ING-006 reduced Col1a1 and α-SMA in IFP fibroblast and IPF lung fragments via GPR84, as demonstrated using GPR84 agonists and siRNA.CONCLUSION: These results suggest that both receptors may be good therapeutic targets in IPF. GPR40 has an early protective role and its activation may reduce epithelial injury and EMT, while GPR84 has a deleterious role in IPF and its inhibition may reduce inflammation and progression to fibrosis. Furthermore, the correlation between both receptors and FVC, DLCO, inflammatory and fibrotic markers, as well as their modulation of expression in cells involved in inflammation/fibrosis, provide strong evidence of the involvement of GPR40 and GPR84 in IPF.
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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 | 0.000 |
| 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".