Proper brain function relies on intricate communications between the neural and vascular systems. Endothelial cells lining the brain blood vessels elaborate a convoluted tubular network, keeping the high energy-consuming neurons within a few microns distance from blood-borne nutrients and dissolved gases. The fluctuating composition of the blood plasma being incompatible with reliable synaptic communications, brain endothelial cells are in addition endowed with a set of molecular, cellular and metabolic adaptations that stringently orchestrate the molecular and cellular transit at the interface between the brain and the circulatory system. Collectively called the blood-brain barrier (BBB), they result from complex and dynamic communications within the neurovascular unit and ensure brain homeostasis. Through its neuroprotective function, the BBB represents a stubborn obstacle for CNS drug delivery, impeding an overwhelming majority of neuroactive molecules from reaching effective concentrations in target brain regions. Conversely, BBB breakdown contributes to a large set of neurological disorders, including stroke and neurodegenerative diseases. Therefore, we need to better understand neurovascular signaling in health and disease. Our laboratory investigates three main research topics:
During embryogenesis, endothelial cells acquire organ-specific characteristics to adapt to the requirements of the perfused organs and tissues. The brain vascular microenvironment serves as a paradigm for extreme blood vessel specialization (blood-brain barrier, BBB), where endothelial cell adaptation appears to be under direct control of a distinct angiogenic program. Recent evidence suggests that brain angiogenesis and the expression of some BBB markers are temporally and functionally coupled. Both processes appear not to be genetically ‘hard-wired’ but rather induced by neuroepithelium-derived cues. Only in recent years have some of the molecular pathways that initiate brain angiogenesis and govern blood-brain barrier formation been revealed. Identifying these organ-specific angiogenic regulators and ordering them into pathways may constitute an unique opportunity to modulate brain vessel formation in brain disease. We explore these pathways in zebrafish embryos through a combination of targeted mutagenesis (CRISPR/cas9, TALEN), genetic mosaics and single-cell resolution real-time imaging.
A key challenge for the treatment of brain diseases is overcoming the difficulty of delivering diagnostic or therapeutic agents to specific regions of the brain. Chief amongst these obstacles is the neuroprotective Blood-Brain Barrier (BBB), both a physical and metabolic barrier to most macromolecules and small compounds. We explore BBB formation and function in the genetically tractable zebrafish model to improve our understanding of the basic molecular and cellular mechanisms that regulate brain microvasculature permeability in vertebrates, with the overarching goal to develop innovative strategies for drug or gene targeting to the injured or diseased brain.
Infections of the central nervous system result in significant morbidity and mortality world-wide and treatments available to combat these incapacitating conditions are often lacking. The mechanisms by which peripherally circulating pathogens overcome host immunity and cross the protective brain barriers to reach the central nervous system remain poorly understood. We use African trypanosomes (Trypanosoma brucei spp) as prototypical model organisms to investigate the molecular dialogue between the parasite and its hosts during the process of infection and brain invasion.