ID: h-8e3748fe5c
Hypothesis
Chronic mTORC1-ULK1 signaling blocks autophagy initiation in irradiated pericytes
DNA damage and SASP signaling keep initiation suppressed, producing a durable upstream autophagy defect.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
DNA damage and SASP signaling keep initiation suppressed, producing a durable upstream autophagy defect.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Growth Factor Signaling<br/>PI3K or AKT Pathway"]
B["mTORC1 Activation<br/>Rheb GTPase Mediated"]
C["S6K1 or 4EBP1 Phosphorylation<br/>Protein Synthesis Upregulation"]
D["Autophagy Inhibition<br/>ULK1 or ATG13 Suppression"]
E["Cap-Dependent Translation<br/>Synaptic Plasticity Proteins"]
F["mTORC2 or AKT Ser473<br/>Cell Survival and Metabolism"]
G["mTOR Inhibitor<br/>Rapamycin or Torin1"]
A --> B
B --> C
B --> D
C --> E
E --> F
G -.->|"inhibits"| B
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
⚖️ Evidence Matrix5 supports1 contradicts
Supports
mTORC1-dependent phosphorylation of ULK1 regulates autophagy initiation.
Supports
mTORC1-mediated feedback inhibition of autophagy in metabolic stress.
Supports
mTORC1-ULK1 signaling axis in autophagy initiation under nutrient stress.
Contradicts
mTOR activation may be transient and not the durable causal lesion.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MTOR
No curated PDB or AlphaFold mapping for MTOR yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MTOR 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 MTOR.
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
↔
Stable
7d Momentum
▼ 0.5%
Volatility
Low
0.0038
Events (7d)
3
Price History
▼7.4%💾 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 DNA damage signaling is attenuated using ATM inhibitor (KU-60019, 5 µM) in irradiated mouse brain pericytes THEN mTORC1 activity will decrease and autophagy initiation markers will normalize, withi | Reduced p-S6K1(T389) to <30% of irradiated control levels, restored p-ULK1(S317) to ≥70% of non-irradiated baseline, and increased autophagosome count (GFP-LC3 | — no observation — | pending | 0.55 |
| IF mTORC1 is pharmacologically inhibited (rapamycin, 100 nM) in irradiated human brain pericytes THEN autophagy initiation will be restored, as evidenced by increased LC3-II/LC3-I ratio and enhanced U | Increased LC3-II/LC3-I ratio (>2-fold) and elevated p-ULK1(S317) (>1.5-fold) in irradiated pericytes treated with rapamycin versus vehicle control | — no observation — | pending | 0.65 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF mTORC1 is pharmacologically inhibited (rapamycin, 100 nM) in irradiated human brain pericytes THEN autophagy initiation will be restored, as evidenced by increased LC3-II/LC3-I ratio and enhanced ULK1 S317 phosphorylation, within 60 minutes of treatment.
Predicted outcome: Increased LC3-II/LC3-I ratio (>2-fold) and elevated p-ULK1(S317) (>1.5-fold) in irradiated pericytes treated with rapamycin versus vehicle control
Falsification: LC3-II/LC3-I ratio remains unchanged (<1.2-fold increase) and p-ULK1(S317) does not increase in irradiated pericytes after mTORC1 inhibition, indicating autophagy initiation remains blocked despite mT
pendingconf 55%
IF DNA damage signaling is attenuated using ATM inhibitor (KU-60019, 5 µM) in irradiated mouse brain pericytes THEN mTORC1 activity will decrease and autophagy initiation markers will normalize, within 48 hours of treatment.
Predicted outcome: Reduced p-S6K1(T389) to <30% of irradiated control levels, restored p-ULK1(S317) to ≥70% of non-irradiated baseline, and increased autophagosome count
Falsification: p-S6K1(T389) remains elevated (>80% of irradiated baseline) and p-ULK1(S317) does not recover after ATM inhibition, indicating DNA damage signaling maintains mTORC1-ULK1 dysregulation independently
▸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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