A Machine Learning-3D Microvessel Platform Identifies Kinase Targets Restoring Blood-Brain-Barrier Endothelial...

Area of Science:

• Neuroscience
• Biotechnology
• Pharmacology

Background:

• Traumatic brain injury (TBI) disrupts the brain endothelial barrier, leading to edema and neurological deficits.
• Current therapies for TBI lack mechanism-guided approaches to stabilize brain vessels.

Purpose of the Study:

• To develop and utilize a 3D human brain endothelial vessel platform for mechanistic analysis of blood-brain barrier (BBB) function.
• To identify kinase pathways and drug candidates for stabilizing the BBB in TBI.

Main Methods:

• A 3D perfusable human brain endothelial vessel platform was used to assess responses to thrombin and TBI patient plasma.
• Machine learning-guided kinase analysis identified key signaling pathways involved in BBB integrity.
• Screening of kinase inhibitors to reverse TBI-induced endothelial barrier breakdown.

Main Results:

• The 3D platform enabled quantifiable assessment of macromolecular barrier function.
• Specific kinase pathways associated with BBB stabilization and disruption were identified.
• Kinase inhibitors that reversed TBI plasma-induced leakage and compounds that exacerbated endothelial loss were nominated.

Conclusions:

• The study establishes a novel platform for precision vascular therapeutics in TBI.
• The approach links patient plasma phenotypes to endothelial barrier responses and kinase signaling.
• This framework offers a versatile strategy for therapeutic discovery across neurovascular disorders.