Mechanisms of Blood-Brain Barrier Transporter Regulation: New Avenues for Understanding and Treating Neurodegenerative Disorders

The blood-brain barrier (BBB) is a dynamic endothelial interface that separates the bloodstream from the brain, and it contains many transporter proteins that maintain homeostasis by shuttling biomolecules between each compartment. Deregulation of BBB transporter expression is observed in many neurodegenerative diseases, and BBB transporters can either enhance or hinder drug permeation into the brain depending on their relative expression and activity. However, the molecular cues and signaling networks that influence these transporters are poorly understood, making it difficult to determine how transporters are naturally regulated and subsequently altered by disease. The focus of this project is to use cell engineering strategies to systematically deconstruct mechanisms that govern BBB transporter expression and regulation. Our overall goal is to better understand how BBB dysfunction impacts neurodegeneration, which may inform future treatment strategies.

The team developed new approaches for constructing human blood-brain barrier models and unveiled a mechanism for how reactive astrocytes cause blood-brain barrier dysfunction. In ongoing work, they completed an arrayed CRISPR screen for regulators of GLUT1 transporter expression. They will validate their GLUT1 CRISPR screen across multiple model systems and develop custom small molecule biosensors to enable CRISPR screening of regulators of transporter function as a complement to expression.