Genetic dissection of airway responsiveness and its impact on the susceptibility to allergic asthma
Bibliographic record
Abstract
Asthma is a chronic and inflammatory disease of the airways determined by genetic and environmental factors which trigger an uncontrolled immune response. Airway hyperresponsiveness (AHR) is inherited as a complex trait and associated with asthma. We assessed AHR in naïve A/J and C57BL/6J mice using the non-invasive method and demonstrated its correlation with invasive method evaluating AHR in non-sensitized mice. Aditionally, we studied the genetic causes underlying AHR using six F2 backcrosses generated from recombinant congenic strains (RCS) created from A/J and C57BL/6J parental strains. Our genetic study allowed us to narrow down the significant regions previously identified in the RCS, as associated with AHR. Quantitative trait loci analysis of BcA86xC57BL/6J (F2) and BcA86xC3H/HeJ (F2) crosses shows 3 significant regions on chromosome 12. These significant regions contain 232 genes, of which 9 genes have been identified as potential candidates. Those genes include the Arhgap5, Foxa1, Clec14a, Ctage5, Rtn1, Gpx2, Rsad2, Prkd1 and Adam21. Additionally, increased levels of secretory leukocyte protease inhibitor (SLPI), an anti-inflammatory mediator, have been observed in asthmatic patients compared to healthy controls. We investigated the role of SLPI in the development of phenotypes associated with allergic asthma and the effect of resiquimod on SLPI expression. Our results demonstrated that over expression of SLPI leads to a lower degree of airway inflammation and higher lung resistance, whereas the ablation of SLPI has the opposite effect on allergic asthma phenotypes. We also demonstrated that the treatment with resiquimod is independent of SLPI expression. Overall, the results presented in this thesis demonstrate how the non-invasive method is a reliable tool for the assessment of AHR in naïve A/J and C57Bl/6J mice. Furthermore, loci on mouse chromosome 12 are linked to the susceptibility to develop AHR. Candidate genes have been identified in these loci and remain to be explored. Finally, we demonstrate the immunoregulatory activity of SLPI in the airways by diminishing inflammation and improving lung function in allergic asthma. Taken together, our results provide a better understanding of the inheritance and molecular mechanisms of phenotypes of asthma as well as provide insights for the design of new therapies.
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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 | 0.001 | 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) | 0.007 | 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".