Research vision

I hypothesize that blood-brain barrier dysfunction in stroke and epilepsy is not a uniform capillary-only event, but a segment-specific process involving arterial, capillary, and venous endothelial states. In this model, vulnerable vascular segments shift from a restrictive barrier program marked by junctional and transport regulators such as CLDN5, OCLN and MFSD2A toward a more permissive, transcytosis-associated state involving CAV1, CAVIN1 and related caveolar pathways.

I further propose that extracellular matrix composition, vascular basement membrane signals, mural-cell interactions and inflammatory stress determine where and when this switch occurs along the arteriovenous axis.

A central aim is to define whether arterial and arteriole-associated endothelial programs contribute directly to barrier instability, tissue vulnerability and disease propagation. I am particularly interested in whether disease-associated RNA editing events alter genes involved in endothelial transport, junctional stability, extracellular matrix signaling or mural-endothelial communication.

I hypothesize that diet influences stroke and epilepsy susceptibility by remodeling plasma composition and thereby reprogramming blood-brain barrier state. Rather than viewing the BBB as a static wall, this framework treats it as a dynamic sensing interface.

Distinct dietary and metabolic states may alter the balance between selective endothelial transport, barrier restriction, inflammatory activation and nonspecific transcytosis. Circulating triglycerides, ketone bodies, insulin, leptin, short-chain fatty acids and inflammatory cytokines are predicted to converge on BBB regulators such as SLC16A1/MCT1, MFSD2A, VCAM1, CLDN5, OCLN and caveolar transport pathways. These changes may influence seizure threshold, stroke vulnerability, vascular repair and long-term neuroinflammatory remodeling.

By integrating plasma profiling, transcriptomics, imaging and disease phenotyping, I aim to understand how diet and circulating factors reshape endothelial and gliovascular states — and whether specific plasma signatures can predict or modify brain vulnerability.

I am interested in whether RNA editing can be used as a mechanistic and therapeutic strategy to modify disease-relevant gliovascular pathways. One long-term concept is to use chemically optimized antisense oligonucleotides to recruit endogenous ADAR enzymes to specific RNA targets involved in astrocyte coupling, endothelial regulation and blood-brain barrier function.

As a proof-of-concept strategy, ADAR-recruiting oligonucleotides could be designed to hybridize to selected regions of connexin43 mRNA, creating a short double-stranded RNA substrate that directs site-specific A-to-I editing. Editing the target adenosine in serine codons such as S255 or S368 could, in principle, recode these sites to glycine-like codons. Because glycine lacks the hydroxyl group required for phosphorylation, this approach could test whether preventing seizure-associated phosphorylation at these connexin43 residues preserves astrocytic gap-junction coupling.

This is biologically important because connexin43 phosphorylation and redistribution are linked to impaired astrocyte network communication, altered channel regulation, disrupted homeostatic buffering and gliovascular dysfunction in epilepsy — a mechanism my own earlier work established.