Astrocyte-produced PGE2 (via COX2 induction) engages microglial EP2 receptors, elevating cAMP and activating PKA. PKA phosphorylates NF-κB p65(S276), altering transcriptional kinetics. Simultaneously, PKA activates SIRT1, which deacetylates H4K16 at trained enhancers, destabilizing the epigenetic memory complex (BET proteins + BRD4). Strong pharmacological tractability due to existing EP2 agonists.
Curated pathway from expert analysis
flowchart TD
A["NAD+ Availability<br/>NAMPT-Dependent"]
B["SIRT1 Activation<br/>NAD+-Dependent Deacetylase"]
C["PGC1alpha Deacetylation<br/>Mitochondrial Gene Activation"]
D["Mitochondrial Biogenesis<br/>Oxidative Phosphorylation"]
E["FOXO Deacetylation<br/>Antioxidant Response"]
F["NF-kB p65 Deacetylation<br/>Inflammation Suppression"]
G["Tau Deacetylation<br/>Proteasomal Clearance"]
H["Neuroprotection<br/>Extended Lifespan"]
A --> B
B --> C
B --> E
B --> F
B --> G
C --> D
D --> H
E --> H
F --> H
G --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for PTGER2 yet. Search RCSB →
Median TPM across 13 brain regions for PTGER2 (EP2) → ADCY → cAMP → PRKA (PKA) → SIRT1 from GTEx v10.
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 PTGER2 (EP2) → ADCY → cAMP → PRKA (PKA) → SIRT1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF EP2 agonist treatment is administered to LPS-primed microglia, THEN SIRT1 deacetylase activity will increase by ≥30% and H4K16ac levels at trained enhancers (Il6, Tnf promoters) will decrease by ≥5 | SIRT1 activity assay shows ≥30% increase; ChIP-qPCR reveals ≥50% reduction in H4K16ac at Il6/Tnf trained enhancers; BRD4 ChIP-qPCR shows ≥40% reduced occupancy | — no observation — | pending | 0.60 |
| IF microglial EP2 receptors are activated with a selective agonist (butaprost, 10 μM) for 48 hours following LPS priming (10 ng/ml, 24h), THEN the inflammatory cytokine response (IL-6, TNF-α) to a sec | ≥40% reduction in IL-6 and TNF-α secretion upon restimulation in EP2-agonist-treated primed microglia relative to vehicle controls | — no observation — | pending | 0.65 |