Abstract 677: The Role of Discoidin Domain Receptor 1 in Vascular Calcification in Atherosclerosis and Diabetes
Bibliographic record
Abstract
Background: Atherosclerosis and diabetes share many common pathogenic mechanisms. Vascular calcification is a common and severe complication in patients with atherosclerosis and type-2 diabetes (T2D), and occurs when vascular smooth muscle cells (VSMCs) trans-differentiate into osteoblast-like cells, in a process driven by runt-related transcription factor-2 (RUNX2). Our laboratory has recently discovered that Discoidin Domain Receptor-1 (DDR1) deletion reduces vascular calcification in vivo in Ldlr -/- mice. Additionally, we have shown that RUNX2 activity is reduced in Ddr1 -/- VSMCs. However, little is known about the mechanism by which DDR1 mediates calcification and RUNX2 activity. Rationale: The insulin signaling pathway plays an important role in T2D and VSMC function. It has recently been discovered that PI3K binds to the DDR1 tyrosine kinase domain upon DDR1 activation. Hypothesis: DDR1 promotes vascular calcification by inducing RUNX2 activity via the PI3K/Akt signaling pathway in T2D. Methods/Results: To study the role of DDR1 in vascular calcification in T2D, Ldlr -/- (SKO) and Ldlr-/-; Ddr1 -/- (DKO) mice were placed on a modified Western diet (40% fat, 43% carbohydrates, 0.5% cholesterol) for 12 weeks. Oil Red-O staining of the descending aorta showed reduced plaque burden in DKO mice (9.1±2.7% vs 4.4±2.9% surface area; p<0.05). Measurements of vascular calcification are ongoing. To determine the mechanism by which DDR1 modulates VSMC calcification, primary VSMCs collected from Ddr1 +/+ and DDR1 -/- mice were cultured in osteogenic media for 12 days to induce calcification. Proliferation and calcification were significantly reduced in DDR1 -/- VSMCs. Additionally, DDR1 -/- VSMCs showed significantly reduced p-Akt levels when stimulated with insulin. Significance: Current treatments for vascular calcification are non-specific and often pose a risk to bone health. This is the first study to test the role of DDR1 in vascular calcification in an animal model of T2D, which will provide novel insight into the mechanism of vascular calcification and uncover new potential therapeutic approaches.
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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) | 0.004 | 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".