Direct pharmacological targeting of BMAL1/CLOCK heterodimers in microglia to restore circadian control over inflammatory gene expression
Auto-built from this analysis's top knowledge-graph edges.
graph TD
ARNTL["ARNTL"] -->|transcriptionally| NLRP3["NLRP3"]
circadian_disruption["circadian disruption"] -->|causes| neuroinflammation["neuroinflammation"]
IL1R1["IL1R1"] -->|mediates| Microglial_priming["Microglial priming"]
anti_TNF_drugs["anti-TNF drugs"] -->|targets| neuroinflammation_1["neuroinflammation"]
inflammation["inflammation"] -->|causes| Microglial_priming_2["Microglial priming"]
microglial_priming["microglial_priming"] -->|causes| neurodegeneration["neurodegeneration"]
NR1D1["NR1D1"] -->|represses| NFKB1["NFKB1"]
IL1R1_3["IL1R1"] -->|mediates| microglial_priming_4["microglial_priming"]
circadian_disruption_5["circadian_disruption"] -->|causes| neuroinflammation_6["neuroinflammation"]
CSNK1D["CSNK1D"] -->|phosphorylates| PER1["PER1"]
MMP9["MMP9"] -->|remodels| extracellular_matrix["extracellular_matrix"]
IL1R1_7["IL1R1"] -->|modulates| positive_feedback_loops["positive_feedback_loops"]
style ARNTL fill:#ce93d8,stroke:#333,color:#000
style NLRP3 fill:#ce93d8,stroke:#333,color:#000
style circadian_disruption fill:#4fc3f7,stroke:#333,color:#000
style neuroinflammation fill:#4fc3f7,stroke:#333,color:#000
style IL1R1 fill:#ce93d8,stroke:#333,color:#000
style Microglial_priming fill:#4fc3f7,stroke:#333,color:#000
style anti_TNF_drugs fill:#4fc3f7,stroke:#333,color:#000
style neuroinflammation_1 fill:#4fc3f7,stroke:#333,color:#000
style inflammation fill:#4fc3f7,stroke:#333,color:#000
style Microglial_priming_2 fill:#4fc3f7,stroke:#333,color:#000
style microglial_priming fill:#4fc3f7,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style NR1D1 fill:#ce93d8,stroke:#333,color:#000
style NFKB1 fill:#ce93d8,stroke:#333,color:#000
style IL1R1_3 fill:#ce93d8,stroke:#333,color:#000
style microglial_priming_4 fill:#4fc3f7,stroke:#333,color:#000
style circadian_disruption_5 fill:#4fc3f7,stroke:#333,color:#000
style neuroinflammation_6 fill:#4fc3f7,stroke:#333,color:#000
style CSNK1D fill:#ce93d8,stroke:#333,color:#000
style PER1 fill:#ce93d8,stroke:#333,color:#000
style MMP9 fill:#ce93d8,stroke:#333,color:#000
style extracellular_matrix fill:#81c784,stroke:#333,color:#000
style IL1R1_7 fill:#ce93d8,stroke:#333,color:#000
style positive_feedback_loops fill:#4fc3f7,stroke:#333,color:#000No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for ARNTL yet. Search RCSB →
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 ARNTL.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF pharmacological activator of BMAL1/CLOCK heterodimers is administered to primary mouse microglia during inflammatory stimulation THEN a ~24-hour circadian oscillation in inflammatory gene expressio | Restoration of rhythmic inflammatory gene expression with significant oscillation amplitude (>2-fold change between peak and trough) and reduced absolute cytoki | — no observation — | pending | 0.72 |
| IF microglial-specific ARNTL (BMAL1) is genetically knocked down using Cx3cr1-CreERT2;Arntlflox/flox mice THEN the magnitude of LPS-induced neuroinflammatory response will significantly increase (no c | ARNTL-deficient microglia will show loss of diurnal variation in inflammatory markers, elevated baseline IL-1β/TNF-α in hippocampus, and complete resistance to | — no observation — | pending | 0.68 |