DISTINCT ROLES FOR DISCOIDIN DOMAIN RECEPTOR 1 (DDR1) EXPRESSED ON BONE MARROW DERIVED CELLS AND VESSEL WALL CELLS DURINGATHEROGENESIS
Bibliographic record
Abstract
We have recently described a critical role for the discoidin domain receptor 1 (DDR1) collagen receptor tyrosine kinase in the regulation of fibrosis and inflammation during atherosclerotic plaque development. DDR1 isexpressed on both SMCs and macrophages; however the role of DDR1 expressed in these distinct cells during atherogenesis remains unresolved. In the current study, female Ldlr^-/- mice that were either Ddr1^+/+ or Ddr1^-/-were lethally irradiated and reconstituted with bone marrow from male Ddr1^+/+ or Ddr1^-/- donors yielding three groups of chimeric mice: Ddr1^+/+^?^+/+ (control); Ddr1^+/+^?^-/-^ (vessel wall deletion); and Ddr1^-/-^?^+/+ (bone marrow deletion). Chimeric mice were placed on an atherogenic diet for 12 weeks and hadsimilar body weights, total leukocyte counts, levels of Sry chimerism, and fasting plasma triglycerides at sacrifice, although total cholesterol was increased by 42% in Ddr1^+/+^?^-/- mice. Deletion of DDR1 inbone marrow derived cells (Ddr1^-/-^?^+/+) resulted in a 66% reduction in atherosclerotic lesion area in thedescending aorta compared to Ddr1^+/+^?^+/+ mice. Aortic sinus plaquesfrom Ddr1^-/-^?^+/+ mice were 36% smaller than Ddr1^+/+^?^+/+ plaques but the proportion of plaque area occupied by cells and matrix was similar between groups. By contrast, deletion of DDR1 in vessel wall cells (Ddr1^+/+^?^-/-) resulted in a 57% increase in atherosclerosis in the descending aorta. Furthermore, aortic sinus plaques from Ddr1^+/+ ^?^-/- mice had markedly increased fibrillar collagen and elastin accumulation compared to Ddr1^+/+^?^+/+ plaques resulting in a 156% increase in lesion area and reduced SMC and macrophage content. In conclusion, while DDR1 on bone marrow derived cells is required for plaque development, DDR1 expressed on vessel wall cells negatively regulates plaque matrix accumulation and results in the formation of larger lesions with altered cellular composition. Our data suggest a dual role for DDR1 in the regulationof atherogenesis and plaque matrix content.
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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) | 0.001 | 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 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".