Project description
Modelling the blood–brain barrier
The blood–brain barrier (BBB) is a highly selective border that blocks access to the brain for pathogens and toxins. Although it helps maintain brain homeostasis, it also prevents certain medications for CNS disorders from reaching the brain. The EU-funded HumBrain project will build a model of the P-glycoprotein transporter which is located in the BBB endothelial cell membranes and effluxes drugs out of the brain. Through simulation of the molecular dynamics of this transporter with various substrates and inhibitors, scientists hope to understand the mechanism underlying BBB selectivity. Apart from providing fundamental knowledge, the project's results will pave the way for the design of the next generation of CNS modulators.
Objective
The blood-brain barrier (BBB) is a complex interface that separates the central nervous system (CNS) from the circulatory system and serves to maintain brain homeostasis. There are native P-glycoprotein (P-gp) transporters embedded in the BBB endothelial cell membranes, which play a fundamental role in effluxing out xenobiotics. Such protections come at a steep price, since the BBB is a key roadblock in the delivery of treatments for CNS disorder, including brain tumors and Alzheimer’s, while the P-glycoprotein transporter reduces the effectiveness of chemotherapeutics and is responsible for the development of multidrug resistance (MDR).
The HumBrain project will build the first atomistic model of a human P-gp pump embedded in a realistic model of the BBB membrane, and use molecular dynamics simulations in combination with novel free-energy techniques to provide a mechanism for the modulation of the P-gp pump by substrates and inhibitors, in order to address the origins of multidrug resistance and the origins of the high selectivity of the BBB membranes to molecules. This will be complemented by coarse-grained models to address the issue of protein-lipid modulation and alternative ways to turn off the P-gp. The models will be of sufficiently realistic representation to serve as a starting point for translational research to aid in the experimental development of the next generation CNS modulators and targets.
The HumBrain project will be carried out by an experienced researcher who worked on membrane proteins during his PhD thesis in the UK and the BBB during his postdoc in the USA in conjunction with an experimental laboratory. The experienced researcher will work with a supervisor in Denmark who has a strong background in modelling complex membranes, including neuronal membranes, as well as membrane proteins, and will benefit from the strong network of simulations present in Denmark, while bringing his expertise from USA and the UK with him.
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
8000 Aarhus C
Denmark