Dong, J.-f. | bioRxiv Science

bioRxiv2026

OmicGlaze: Spatial Multi-Omic Mapping of Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of mortality and long-term disability worldwide, giving rise to complex neurological complications that impact millions of individuals each year. Cellular stress and neuronal injury vary dramatically across cortical layers, vascular niches, and between the ipsilateral (injured) or contralateral (uninjured) hemispheres. There is a critical need for quantitative measures that capture the spatial distribution of injury-induced cellular changes, as well as the gene regulatory elements that drive them. Here, we developed OmicGlaze, an experimental and computational workflow for systematically profiling the spatial transcriptome and epigenome of mouse brains following mild traumatic brain injury. We established a spatial scoring system, and identified region-specific biological processes post injury, including changes in neuronal activities, cellular stress, immune response, and gliosis. Spatial assay for transposase-accessible chromatin with sequencing (Spatial ATAC-seq) generated the first epigenetic map of traumatic brain injury near single-cell resolution. Notably, we identified the Activator Protein-1 family transcription factor Atf3 as a key gene regulator of injury-induced cellular stress. Together, these spatial multi-omics analyses revealed gene regulatory network in TBI and provided a broadly applicable framework for dissecting cellular and molecular mechanisms underlying complex neurological disorders.

systems biology↗

bioRxiv2025

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

Disruption of the brain endothelial barrier is a hallmark of traumatic brain injury (TBI), and contributes to cerebral edema, coagulopathy, and delayed neurological deficits, yet there are no mechanism-guided therapies that directly stabilize human brain vessels. Here we used a three-dimensional (3D) human brain endothelial vessel platform with quantifiable macromolecular barrier function to assess responses to thrombin and plasma from patients with TBI. This endothelial-focused 3D system isolates the central cellular regulator of blood-brain barrier function and enables mechanistic analysis of endothelial signaling and drug responses as a foundation for personalized vascular therapeutics. By integrating this platform with machine learning-guided kinase analysis, we identified kinase pathways associated with barrier stabilization versus disruption and nominated inhibitors that reversed thrombin- and TBI plasma-induced leakage as well as compounds that exacerbated endothelial loss. This work establishes an important first step toward precision vascular therapeutics in TBI, by linking patient-derived plasma phenotypes to specific endothelial barrier responses and pharmacologically tractable kinase signaling, and it provides a generalizable framework for mechanistic drug discovery across neurovascular disorders. SIGNIFICANCE STATEMENTBlood-brain barrier (BBB) disruption drives cerebral edema, coagulopathy, ischemia, and neurological deficits after TBI. Targeting kinases as therapeutics is promising but challenged by complex inhibitor profiles and patient variability. We present a machine learning-guided platform built on 3D perfusable human brain endothelial-centric microvessels to systematically screen and select kinase inhibitors that reverse TBI-induced endothelial barrier breakdown. By pinpointing key kinase and gene regulators and demonstrating restoration of endothelial barrier integrity in patient-derived plasma models, our approach provides a transformative strategy for stabilizing the endothelial barrier after TBI and offers a versatile framework for therapeutic discovery across neurovascular disorders.

bioengineering↗