ID: h-780cbb9e6f
Hypothesis
Radiation drives pericyte senescence through lysosome acidification failure and stalled late-stage autophagy
Autophagosomes still form after irradiation, but damaged lysosomes cannot clear cargo, sustaining ROS and SASP output.
EvidencePending (0%)📖 6 cit🗣 1 debates✓ 6 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
Autophagosomes still form after irradiation, but damaged lysosomes cannot clear cargo, sustaining ROS and SASP output.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["mTORC1 Hyperactivation<br/>Nutrient/Growth Signals"]
B["TFEB Phosphorylation<br/>Ser211 by mTORC1"]
C["14-3-3 Sequestration<br/>Cytoplasmic Retention"]
D["Lysosomal Biogenesis<br/>Blocked"]
E["Autophagic Flux<br/>Impaired"]
F["Tau/Amyloid Aggregate<br/>Accumulation"]
G["TFEB Activation<br/>Rapamycin or MCOLN1"]
H["Nuclear TFEB<br/>CLEAR Gene Expression"]
G --> H
H -.->|"rescues"| D
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
⚖️ Evidence Matrix6 supports1 contradicts
Supports
Flux and lysosomal pH assays can sharply test a late-stage autophagy block.
Supports
Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.
Supports
mTORC1-dependent TFEB nucleus translocation and pro-survival autophagy induced by zeolitic imidazolate framework-8.
Supports
Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in Alzheimer's disease models.
Contradicts
Static LC3/SQSTM1 accumulation can be misread without direct flux data.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TFEB
No curated PDB or AlphaFold mapping for TFEB yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TFEB from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TFEB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
$0
Timeline
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🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▼ 0.9%
Volatility
Low
0.0042
Events (7d)
3
Price History
▼12.3%💾 Resource Usage
LLM Tokens
1,500
$0.0045
Total Cost
$0.0045
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF irradiated pericytes exhibit lysosome acidification failure, THEN preventing lysosome acidification with bafilomycin A1 will replicate the radiation-induced senescence phenotype (SA-β-gal positivit | SA-β-gal positive cells ≥40% in 10 Gy irradiated pericytes (vs. <10% in sham); IL-6 concentration in conditioned medium ≥300 pg/mL (vs. <100 pg/mL baseline); in | — no observation — | pending | 0.68 |
| IF primary human brain pericytes are exposed to 10 Gy ionizing radiation, THEN lysosomal pH will increase by ≥0.5 units (deacidification) AND p62/SQSTM1 will accumulate ≥2-fold within 48 hours post-ir | Lysosome pH ≥6.2 (vs. ~5.0 in controls) measured by ratiometric LysoSensor imaging; p62 protein level ≥2-fold elevated by western blot; TFEB remains cytoplasmic | — no observation — | pending | 0.72 |
🔮 Falsifiable Predictions (2)
pendingconf 72%
IF primary human brain pericytes are exposed to 10 Gy ionizing radiation, THEN lysosomal pH will increase by ≥0.5 units (deacidification) AND p62/SQSTM1 will accumulate ≥2-fold within 48 hours post-irradiation, indicating stalled late-stage autophagy.
Predicted outcome: Lysosome pH ≥6.2 (vs. ~5.0 in controls) measured by ratiometric LysoSensor imaging; p62 protein level ≥2-fold elevated by western blot; TFEB remains c
Falsification: Lysosome pH remains ≤5.2 and p62 is degraded normally (autophagy flux intact), OR TFEB translocates to the nucleus indicating compensatory lysosome biogenesis—either result would refute the lysosome a
pendingconf 68%
IF irradiated pericytes exhibit lysosome acidification failure, THEN preventing lysosome acidification with bafilomycin A1 will replicate the radiation-induced senescence phenotype (SA-β-gal positivity ≥40%, IL-6 secretion ≥3-fold) within 96 hours.
Predicted outcome: SA-β-gal positive cells ≥40% in 10 Gy irradiated pericytes (vs. <10% in sham); IL-6 concentration in conditioned medium ≥300 pg/mL (vs. <100 pg/mL bas
Falsification: Bafilomycin A1 treatment does not induce senescence markers comparable to radiation, OR radiation-induced senescence occurs despite preserved lysosome acidification—either would dissociate the propose
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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