Molecular mechanisms regulating the blood-brain barrier

Rapidly growing evidence show that the blood-brain barrier (BBB) is impaired in a wide range of brain diseases, including stroke, monogenic brain disorders, neurodegenerative diseases (e.g. Alzheimer’s) and brain tumors. However, mechanism(s) are unclear. A functional BBB is pivotal for proper neuronal functions, but also of hindrance for drug delivery into the brain.

The goal of BBB research is therefore double: (i) to normalize BBB function in diseases, and (ii) to open the BBB on demand for drug passage.

A major obstacle in achieving this goal is the lack of fundamental knowledge about BBB regulation at molecular and cellular levels.

Our own recent work has contributed seminally to several aspects of these goals: By single-cell analysis, we have provided molecular definitions of the cells that construct the BBB, and we have demonstrated the critical importance of one of these—pericytes—as a key regulator of endothelial barriers.

Building on these pioneering studies, we now propose to 1) uncover the function(s) of the major BBB tight junction protein, Cldn5; 2) analyse the roles of the context-sensitive growth factor Angpt2 in the BBB; and 3) map the changes in the vascular transcriptome and proteome that occur in the BBB following targeted mutagenesis of Cldn5, Angpt2 and pericyte-regulatory genes.

By accomplishing this project, we will deliver a significant knowledge base for understanding physiological, developmental and pathological mechanisms in the brain vasculature.