Abstract TMP97: Rho Kinase Inhibition Blunts Lesion Development in Murine Models of Aggressive <i>Pdcd10/Ccm3</i> Disease Through Rock2
Bibliographic record
Abstract
Introduction: Previously, murine models Ccm1 +/- Msh2 -/- and Ccm2 +/- Trp53 -/- showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by RhoA kinase (Rock) inhibitor fasudil and by simvastatin (with weak pleiotropic Rock inhibition effect). Herein we investigated treatment of the more aggressive Ccm3/Pdcd10 model with these drugs, and higher dose and intensity atorvastatin, and determined which Rock isoform is involved in CCM development and hemorrhage. Hypothesis: Rock inhibition blocks CCM burden in Ccm3 models, through Rock1 or Rock2 isoforms. Methods: The murine model Ccm3 +/- Trp53 -/- was concurrently treated from weaning to 5 months of age with fasudil (100 mg/kg/day in drinking water, n=7), simvastatin (40 mg/kg/day in chow, n=8), atorvastatin (80 mg/kg/day in chow, n=7) or with placebo (n=10). We assessed CCM volume in mouse brains by micro-computed tomography. We then concurrently bred Rock1 +/+ (n=15) and Rock1 +/- (n=17), Rock2 +/+ (n=17) and Rock2 +/- (n=15) mice with Ccm3 +/- mice and assessed respective lesion burden. We further analyzed chronic hemorrhage in CCM lesions by intensity of Perl staining in brain sections. Results: In the Ccm3 +/- Trp53 -/- model, mean CCM lesion volume/brain volume (X 10 3 ) per mouse decreased from 12.2 in placebos to 2.5 (p=0.002) by fasudil, and to 3.0 (p=0.002) by atorvastatin treatment, but was not changed significantly by simvastatin. CCM lesion volume/brain volume (x 10 6 ) per mouse decreased from 19.6 in Ccm3 +/- Rock2 +/+ to 2.3 (p=0.011) in Ccm3 +/- Rock2 +/- animals, and not significantly in Ccm3 +/- Rock1 +/ mice. Hemorrhage intensity per brain was commensurately decreased by Rock 2 but not Rock1 transheterozygocity. Conclusion: CCM lesion development was inhibited by fasudil and atorvastatin but not lower dose and intensity simvastatin therapy. The benefit of Rock inhibition on lesion development and blunting of hemorrhage resulted from effects through Rock2, predominantly expressed in heart and brain, but not Rock1 isoform.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".