PT-014 - A GLOBAL PROTEOMICS ANALYSIS OF THE ONTOGENY OF THE BLOOD-BRAIN BARRIER.

X. Zhou¹, M. Azimi¹, N. Handin², S. Yee¹, P. Artursson², K. Giacomini¹; ¹University of California, San Francisco, San Francisco, CA, USA, ²Uppsala University, Uppsala, Sweden.

Background: Blood–brain barrier (BBB) is crucial in maintaining brain homeostasis and protecting brain from xenobiotics. Through changes in protein expression, specific barrier functions alter during development. The goal of this study was to comprehensively characterize protein expression levels in BBB using human brain microvessels (BMVs) prepared from various age groups.

Methods: BMVs were isolated from twenty-seven healthy donors (neonates to adults) and global proteomics analysis was performed to quantify protein expression levels. Differential expression analysis and Gene Ontology enrichment analysis were used to identify proteins that quantitatively differ between age groups (FDR < 0.05, absolute fold change > |± 1.5| ).

Results: Our global proteomics study identified 292 proteins upregulated with age and many of these proteins were involved in cell-substrates adhesion, a process that is important in BBB formation. In contrast, 441 proteins were downregulated during development. Transporters essential for neurogenesis decreased with age. Among the well-known drug transporters, ABCB1 and ABCC4 exhibited the tendency for reduced protein expression from neonate to adulthood (r2 = 0.191, p < 0.03 for ABCB1).

Conclusion: Our study, for the first time, inclusively identified proteins in BMVs which display age-dependent patterns. These patterns not only explain the physiological changes during human brain development but also suggest drugs may distribute differently into brain with age. These data can be used in physiologically based pharmacokinetic (PBPK) modeling to predict drug dosing with age. Future analyses will explore the mechanisms responsible for ontogenetic changes of protein expression including drug transporters, which may affect pediatric drug dosing.