Regulation of Lgl1 and its role in hyperoxic injury of the newborn lung
Bibliographic record
Abstract
Bronchopulmonary dysplasia (BPD), a leading cause of morbidity in very low birth weight infants, is characterized by an arrest in alveolar development. An improved insight into the genes and mechanisms that regulate alveolarization is essential to enhance our understanding of the lung pathophysiology of BPD. LGL1, is a developmentally regulated, glucocorticoid induced, secreted glycoprotein in the lung. In order to establish the role of Lgl1 in alveolarization, I studied Lgl1 expression in two rat models of oxygen toxicity (BPD) that reproduce many of the characteristic features of BPD. I showed that in hyperoxia, Lgl1 levels are reduced and that these levels normalize during recovery in air. The 5' promoter region of Lgl1 has binding sites for the glucocorticoid (GC), retinoic acid (RA) and vitamin D (Vit D) receptors and for Smad3 (mediates transforming growth factor-beta (TGF-β) signalling), all of which modulate alveolarization and are considered to have a role in neonatal lung injury. Exposure of primary rat lung fibroblasts to GC, RA, Vit D and TGF-β1, alone or in combination, confirmed that all these agents regulate Lgl1 expression. Interestingly, the individual inhibitory effects of Vit D and RA on GC induction of Lgl1 were abrogated when both agents were present. Results of Luciferase assays were consistent with a role for all of these agents in transcriptional regulation. Interestingly, an analysis of the proximity (<50 base pairs) of binding sites for overlapping Vit D and RA receptors to that of the GC receptor identified 81% of promoters in 65 genes (including Lgl1) important in human lung development compared to 48% in a random set of 1000 genes. This suggests that steric hindrance may influence promoter accessibility when more than one of these agents is present simultaneously. In order to further explore the functional role of Lgl1, an Lgl1 knockout mouse model was generated. Absence of Lgl1 is embryonic lethal. Haploinsufficiency for Lgl1 deficiency was associated with a complex phenotype including: goblet cell hyperplasia, mucus production, increased expression of interleukins 4 and 13, elastin fragmentation and disruption of adult lung function. This phenotype was exacerbated by oxygen exposure. The combined results of my studies suggest that Lgl1 deficiency may contribute to neonatal lung injury in BPD.
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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 | 0.000 |
| 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".