Initial BBB disruption from another cause exposes the neurovascular unit to albumin, fibrinogen, and related plasma signals that activate TGF-beta/SMAD stress pathways and drive pericyte senescence secondarily. This creates a feed-forward loop in which senescence is initially downstream but later helps lock in chronic BBB dysfunction.
Curated pathway from expert analysis
flowchart TD
A["Astrocyte-Derived TGF-beta1<br/>Anti-inflammatory Ligand Source"]
B["TGFBR2/TGFBR1 Complex Formation<br/>Microglial Receptor Activation"]
C["SMAD2/3 Phosphorylation<br/>SMAD4 Corepressor Assembly"]
D["RelA/p300 Displacement<br/>NF-kB Enhancer Rewiring"]
E["TNF/IL1B/IL6 Suppression<br/>Trained Immunity Memory Reset"]
F["Homeostatic Microglial State<br/>Inflammatory Tone Resolution"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TGFB1 yet. Search RCSB →
Median TPM across 13 brain regions for TGFB1, TGFBR2, SMAD2, SMAD3 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 TGFB1, TGFBR2, SMAD2, SMAD3.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF adult C57BL/6J mice with controlled cortical impact (CCI) brain injury receive oral TGFBR2 kinase inhibitor (SM16 at 10 mg/kg twice daily) starting 1 hour post-injury for 7 days, THEN we will obser | Pericyte senescence markers (p21, SA-β-gal) will be reduced by ≥40% in TGF-beta-inhibited mice compared to vehicle controls at 7 days post-CCI, while BBB leakag | — no observation — | pending | 0.72 |
| IF we prospectively measure plasma TGFB1 (ELISA) and pericyte-derived exosomal markers (exosomal CD13, exosomal PDGFRB) in acute ischemic stroke patients (n=80, NIHSS 5-20) within 6 hours of onset and | Patients with highest tertile TGFB1 increase will show ≥2-fold higher exosomal senescence markers compared to lowest tertile, and this relationship will remain | — no observation — | pending | 0.68 |