Restoring DF508-CFTR trafficking and activity with epigenetic modifiers
Bibliographic record
Abstract
Cystic fibrosis (CF) is an early onset disease characterized by a defect in the apical chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR). The most common disease causing mutation is a 3 basepair deletion resulting in loss of Phe 508 (ΔF508), which leads to misfolding and efficient endoplasmic reticulum associated degradation (ERAD) of the protein, a hallmark of misfolding diseases. Recently epigenetic modifiers have been shown to alleviate various misfolding diseases suggesting that they may be beneficial for correcting the trafficking defect associated with the ΔF508 mutation of CFTR. We now show that treatment with such epigenetic modifiers can alleviate the ER retention of ΔF508-CFTR to deliver a functional channel to the cell surface in both a culture model (CFBE41o-) and in human primary bronchial epithelial cells isolated from CF patients homozygous for the ΔF508 mutation. Additionally we have identified a single member of a large family of enzymes as the key molecular target of these small molecule epigenetic modifiers. siRNA-mediated knockdown of this protein results in robust correction of the trafficking defect and robust cell surface chloride channel activity. We believe that this correction is a result of an overall alteration of the proteostatic environment of the cell such that multiple CFTR linked pathways are altered to favor increased ER stability, ER export, cell surface delivery and channel activity. DMHutt is supported by fellowships from the Canadian Institutes for Health Research and the Canadian Cystic Fibrosis Foundation.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".