SMALL MOLECULE REGULATORS OF BBB PERMEABILITY
Zebrafish offer a powerful tool to identify novel small molecules that can either increase BBB permeability, thereby granting access to otherwise restricted therapeutics to the brain, or decrease BBB permeability to prevent the entry of neurotoxic agents into the brain. Using novel behavioral assays, we can assess BBB function in 96-well plate format.
As an optically transparent model organism with an endothelial blood-brain barrier (BBB), zebrafish offer a powerful tool to study the vertebrate BBB. We recently captured the dynamics of developmental BBB leakage using live confocal imaging, revealing a combination of steady accumulation in the parenchyma and sporadic bursts of tracer leakage. Electron microscopy studies further revealed high levels of transcytosis in brain endothelium early in development that are suppressed later. The timing of this suppression of transcytosis coincides with the establishment of BBB function. Our findings indicate a conserved developmental program of barrier acquisition between zebrafish and mice.
IDENTIFY MUTANTS WITH BBB DEFECTS
We are interested in identifying new molecular targets that regulate BBB permeability. Using CRISPR mutagenesis and fluorescent tracer leakage assays, we can assess whether loss of gene function leads to altered BBB permeability.