Abstract 16461: Genetic Basis of Severe Pulmonary Arterial Hypertension in a Colony of SU5416 “Hyper-responsive” Sprague-dawley Rats
Bibliographic record
Abstract
Introduction: Our lab has identified a unique sub-strain of Sprague Dawley (SD) rats obtained from a colony of Charles River labs (Montreal, Canada) exhibiting hyper-responsiveness (HR) to the VEGFR2 antagonist, SU5416 (SU). These rats developed severe progressive PAH in response to single injection of SU in absence of CH. In the present study, we investigated genetic basis of hyper-responsive (HR) phenotype in the sub-strain of SD rats. Hypothesis: We hypothesized that hyper-responsiveness to SU was conferred by as yet unknown genetic modifiers that modulate the response to VEFR2 blockade. Methods and Results: Male and female rats were injected with SU (20mg/kg, sc) or vehicle (control). Right ventricular systolic pressure (RVSP) was measured at 7 weeks after SU injection. In absence of CH, 72% (13 of 18) male SD rats demonstrated HR-phenotype and developed severe PAH in response to SU with mean RVSP of 97±18 mmHg; whereas only 27% (7 of 26) of the female rats showed HR-phenotype. Furthermore, crossing non-responsive male and female animals markedly decreased the proportion of HR animals in the F1-generation (HR 15% and 0%. male vs. female, respectively), supporting a possible genetic basis for the HR phenotype. Therefore, we undertook whole genome-wide exome sequencing to identify mutations related to the HR phenotype. This resulted in the identification of a number of mutations unique to the HR SD colony (not found in 40 other background strains) and predicted to have a “high effect” on gene function. Preliminary analysis has identified several candidate genes exhibiting mutations tightly associated with the HR phenotype, including the protein C receptor, hypoxia inducible factor 1α and SP110. These and other potential modifier genes identified by a bioinformatics analysis are currently being validated in a larger population of rats from this SD colony, with and without the HR phenotype. Conclusion: For the first time, we have identified modifier genes that play a critical role in determining susceptibility to development of severe PAH in response to SU alone. These data may provide insight into the nature of potential genetic determinants that may influence the penetrance of the PAH phenotype in humans harboring mutations BMPR2 or in other PAH causing genes.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".