Chandler Est

Vitamin A transport across the Blood Brain Barrier (BBB) is critical for CNS function. However, the mechanism by which Vitamin A (retinol) crosses the BBB is still not understood. Retinol is normally carried throughout the body bound to Retinol Binding Protein 4 (RBP4), which is in complex with another protein, Transthyretin (TTR). Recently, an endothelial surface receptor at the BBB, STRA6, has been identified as an acceptor for retinol via a protein-protein interaction with RBP4. Key binding residues have been identified on STRA6, but the residues involved for RBP4 have not yet been elucidated. However, recent genetic knockout studies seem to contradict the involvement of STRA6 as the means by which retinol crosses the BBB, leading to debate about the mechanism of passage. My research focuses on the necessary protein-protein interactions required for retinol passage across the BBB, including identification of key residues, allosteric interactions or the involvement of additional proteins beyond RBP4 and STRA6, such as TTR. To investigate these interactions, I develop and utilize recombinant protein technology and stem cell derived BBB models that express STRA6.

The second aim which I intend to address in my work is an investigation into the effect of Alzheimer’s Disease (AD) on Vitamin A transport at the BBB. TTR has recently been identified as a scavenger of beta-amyloid peptide (Aβ), and aggregation of this peptide in the brain constitutes the hallmark of AD pathology. Because TTR normally carries retinol via RBP4, scavenging Aβ may cause disturbances in the physiological transport of retinol through the BBB, leading to Vitamin A imbalances. Work elsewhere in AD research has indicated Vitamin A levels are indeed altered in AD patients, and I investigate the mechanisms by which Aβ alters this transport process at the BBB.