Genetic or Pharmacological Induction of the Hypoxia Response Enhances Functional Regeneration Following Peripheral Nerve Injury
Bibliographic record
Abstract
Peripheral nerve injuries (PNIs) occur in 1–3% of patients with traumatic injuries. While peripheral axons have the ability to regenerate at ~1mm/day, the distance over which they must do so means lengthy recovery times, which are associated with regenerative failure due to a decline in supporting cells' ability to maintain axon growth. Successful axonal regeneration depends heavily upon the neuronal response to injury, as well as that of myeloid cells recruited to the damaged nerve. In injured neurons, transcriptomic changes occur which mirror those observed in hypoxia. Hypoxia inducible factors (HIFs) effect these transcriptomic changes; these are governed in turn by prolyl hydroxylase domain (PHD) proteins. Under normoxic conditions, PHDs act as master regulators of the hypoxia response, targeting HIFs for proteasomal degradation. We hypothesize that deleting any or all of the PHDs (PHD1, 2, and 3), or inhibiting PHDs pharmacologically, will induce the hypoxia response and enhance axonal regeneration and functional recovery following PNI. We used global PHD1 knockout, global PHD3 knockout, and heterozygous PHD2 transgenic mice, as well as non‐transgenic mice treated with DMOG, a pan‐PHD inhibitor. We used a sciatic nerve crush model of injury and assessed functional recovery at various time points post‐injury using toe pinch and grasping tests, and electromyography. Using immunohistochemistry we characterized macrophage and axon densities in the nerves after injury. We also assessed DMOG‐induced changes in macrophage phenotype using FACS, RT‐PCR and immunohistochemistry. We found that deletion of PHD1 or PHD3, or inhibition of all three PHDs resulted in earlier functional recovery after injury, increased macrophage infiltration in the injured nerve, an M2‐skewed macrophage phenotype, and enhanced axonal regrowth. In addition, deletion of any of the PHDs, or their inhibition by DMOG, resulted in improved electromyographical responses of the nerve one month post injury. Our findings suggest that functional recovery after peripheral nerve injury can be aided by hypoxia‐independent induction of the hypoxia response. Support or Funding Information Wings for Life; ICORD Blusson Integrated Cures Partnership This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.001 | 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".