Project description
A zebrafish model of the blood–brain barrier
The blood–brain barrier (BBB) is paramount for brain homeostasis since it defines the molecular and cellular transit between the brain and the circulatory system. This is achieved through complex communications between endothelial cells and other components of the neurovascular system. To study BBB permeability, the EU-funded Ctrl-BBB project will employ the zebrafish as a model because of its transparent nature and its capacity to undergo non-invasive genetic analyses. Considering that the BBB prohibits drug delivery into the CNS, understanding how it is regulated will unveil novel therapeutic avenues for various disorders including stroke, multiple sclerosis and neurodegeneration.
Objective
Brain endothelial cells (ECs) are endowed with a set of molecular and metabolic adaptations that stringently orchestrate the molecular and cellular transit between the brain and the circulatory system. These adaptations constitute the blood-brain barrier (BBB) and are pivotal to brain homeostasis and protection. Accordingly, BBB dysfunction is a unifying hallmark of many cerebrovascular diseases, including stroke, multiple sclerosis and neurodegeneration. Healing the BBB to treat to the brain is therefore emerging as a powerful therapeutic avenue for a spectrum of human CNS disorders. In addition, through its neuroprotective function, the BBB represents the main obstacle for CNS drug delivery. There is consequently an urgent need to identify methods to control BBB in health and disease. Of pivotal importance, BBB is not genetically hardwired, but instead results from ongoing neurovascular communications taking place between the ECs and the other components of the neurovascular unit. Shedding light on these communications, and raising our understanding to the mechanistic level will undoubtedly yield transformative therapeutic strategies for human brain disorders. A key obstacle in the study of BBB permeability resides in its complex regulation across cells and tissues. This complexity cannot be recapitulated in cell culture experiments. Our laboratory has recently identified and validated the transparent zebrafish as ideally suited to facilitate these studies, by empowering non-invasive genetic analyses of BBB function under normoxia. Together with a conserved BBB genetic instruction program, the zebrafish cerebrovasculature qualifies as a an alternative “miniature BBB model” where neurovascular communication can be studied at an unprecedented pace. Ctrl-BBB will pioneer synergistic approaches between the zebrafish and the mouse model, to bring BBB research in the era of highly parallel genetic approaches and BBB-focused therapeutic strategies for brain disorders.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
1050 Bruxelles / Brussel
Belgium