S100B operates as a pathogenic DAMP in the perivascular space, binding RAGE on brain endothelial cells to trigger NF-κB-mediated downregulation of claudin-5 and occludin, creating a self-amplifying BBB disruption loop. Longitudinal plasma S100B slope — not single timepoint — is the mechanistically meaningful metric.
Curated pathway from expert analysis
flowchart TD
A["Reactive Astrocyte S100B<br/>Damage-Associated Signal"]
B["RAGE Engagement<br/>NF-kB Activation"]
C["Claudin-5 Suppression<br/>Barrier Junction Weakening"]
D["BBB Permeability Increase<br/>Endothelial Dysfunction"]
E["Peripheral Inflammatory Entry<br/>Neurovascular Injury"]
F["Chronic Neuroinflammation<br/>Feed-Forward BBB Damage"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for S100B yet. Search RCSB →
Median TPM across 13 brain regions for S100B 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 S100B.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF patients with traumatic brain injury (TBI) are stratified by longitudinal plasma S100B slope (increasing >20% per day vs. decreasing <5% per day) over 5 days post-injury, THEN the increasing-slope | Ktrans values and QAlb will be ≥50% higher in the increasing S100B-slope group, with correlation coefficient r≥0.6 between S100B slope magnitude and permeabilit | — no observation — | pending | 0.65 |
| IF a RAGE antagonist (e.g., FPS-ZM1) or function-blocking anti-S100B antibody is administered to mice with verified plasma S100B elevation (>50 ng/mL), THEN brain endothelial NF-κB nuclear translocati | ≥50% reduction in brain endothelial NF-κB activation and ≥80% restoration of claudin-5 expression compared to vehicle-treated controls with matched S100B levels | — no observation — | pending | 0.70 |