HTRA1-dependent proteolysis induces age-related retinal degeneration and exacerbates choroidal neovascularization
Bibliographic record
Abstract
Polymorphisms in the ARMS2/HTRA1 locus on chromosome 10 enhance the risk of geographic atrophy and macular neovascularization, the advanced forms of age-related macular degeneration (AMD). Although HTRA1 mutations have been associated with microvascular defects in the brain, it remains unclear whether changes in HTRA1 expression contribute to AMD pathophysiology. In this study, we showed that, in AMD donor eyes, HTRA1 protein accumulated around the retinal pigment epithelium (RPE)/photoreceptor lesions. We then demonstrated that overexpression of catalytically active, but not catalytically inactive, HTRA1 in RPE cells in mice induced age-dependent loss of photoreceptors, inflammation and a decline in photoreceptor functional responses. This retinal degeneration was not exacerbated when the mice were exposed to phototoxic stress in the constant light exposure preclinical model. However, mice overexpressing catalytically active HTRA1 had significant exacerbation of laser-induced choroidal neovascularization lesions. Finally, as substrate processing may define the molecular basis for HTRA1-induced retinal degeneration, we initiated a proteomics approach and identified the visual cycle key player RBP3 as a disease-relevant HTRA1 substrate in the retina.
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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".