Dysregulated Glomerular Proteins in 1-Day-Old Col4a3 Knockout Mice
Bibliographic record
Abstract
Background: Alport syndrome (AS) is a hereditary disorder caused by pathogenic variants in COL4A3, COL4A4 and/or COL4A5, encoding the α3α4α5 chains of type IV collagen typically expressed in the mature glomerular basement membrane (GBM) of the kidney. In AS due to truncating variants, podocytes do not form the α3α4α5(IV) basement membrane and instead, there is persistence of the flexible α1α1α2(IV) trimer normally present during development. To understand the earliest mechanisms of disease in AS, we elected to study glomerular changes in Col4a3 -/- (knockout; KO) mice at postnatal-day 1 (P1), when trimer switching is occurring. Methods: P1 Col4a3 KO and wildtype mouse glomeruli were isolated using Dynabeads. Protein extracts from glomerular samples were subjected to mass spectrometry. Pathway analysis was performed using Gene Ontology and protein interactors were identified using STRING. Results: More than 1,000 proteins from glomerular extracts were significantly dysregulated in P1 female KO compared to wildtype. In assessing protein-protein interactions between significantly dysregulated proteins, those with the greatest number of interactors included ACTB, GAPDH, ATP5B, EEF2, and SDHA. Over 70 pathways were identified as significantly different in female P1 KO compared to wildtype. Notably, these pathways were related to K63-linked deubiquitinase activity, alternative mRNA splicing, via the spliceosome, establishment or maintenance of transmembrane electrochemical gradient, actin filament binding, and NF-κB binding. In P1 male KO compared to wildtype, 17 proteins from glomerular extracts were identified as significantly dysregulated but no significantly different pathways were identified. Conclusion: Pathways related to alternative splicing, cell maintenance, actin binding, and inflammation are dysregulated in the glomerulus at the earliest stage of disease in Col4a3 KO mice. These dysregulated pathways will be further explored to understand biological mechanisms in disease and to inform therapeutic development in the future. Funding: Private Foundation Support, Government Support – Non-U.S.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| 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".