Bainton Lab
Research Summary
In the central nervous system (CNS) of vertebrates, the blood-brain barrier (BBB), comprised of the vascular endothelium and astrocytic glia, ensures a privileged or protected neuronal environment. This organization presents a challenge to the barrier, as the competing needs for neuroprotection and metabolic homeostasis greatly limit natural diffusion and mixing of nutrients, metabolites and drugs. Further, the sophisticated biology of the BBB influences drug responses, both as a pure pharmacokinetic barrier and as a site of drug action that could modulate internal brain function. BBB processes are controlled by discretely localized regulatory systems, but how competing physiologic functions are integrated is uncertain. We discovered a novel G-protein coupled receptor (GPCR)-based regulatory system in the Dm BBB centered on the Moody GPCR. Moody is the first transmembrane signaling protein to be described at the humoral-CNS interface and the first to link barrier glia with regulation of behavioral function. This connectionwith a vast network of g-proteins and their upstream as well as downstream effectors suggested to us that the Dm BBB is a dynamic structure that controls drug exclusion properties and modulates brain responses. We have shown that Dm BBB anatomy has unique advantages for the simultaneous study of different BBB physiologies, yielding unique insights into the interrelationship of humoral-barrier epithelium and associated glia
In one applied aspect of our work, we are interested in understanding how an organism defends itself against xenobiotic incursion as well as how dysfunction of such a xenobiotic barrier may contribute to CNS pathology. The barrier combines two distinct (and likely mechanistically linked) properties. The first is a physical barrier comprised of tight paracellular borders (septate junctions in Dm; tight junctions in vertebrates). The second is a transport barrier that extrudes compounds that passively or actively diffuse across the barrier. In vertebrates, the latter function is mediated by members of the large and conserved ABC family of ATP-dependent transporters including the gold-standard multi-drug resistance transporter usually referred to as Mdr1 or P-glycoprotein (PgP). This family, in conjuction with the diffusion barrier and other players such as the OATP transporters, maintain chemical separation of physiologic compartments but also induce potent drug penetration problems in clinical settings. The regulation and integration of drug transport physiology into complex multi-faceted blood brain barrier (BBB) functions is poorly understood and difficult to study in vertebrate model systems. Drosophila offers unique advantages for the study of neuroprotective barriers, as active-drug transport and passive-diffusion barrier properties can be measured simultaneously in live animals.
