Projektbeschreibung
Modell der Blut-Hirn-Schranke in der Anwendung
Die Blut-Hirn-Schranke ist eine hochselektive Barriere, die das Gehirn vor Krankheitserregern und Toxinen schützt. Auch wenn diese Schranke zur Homöostase des Gehirns beiträgt, verhindert sie jedoch gleichermaßen, dass bestimmte Arzneimittel gegen Erkrankungen des Zentralnervensystems das Gehirn erreichen. Das EU-finanzierte Projekt HumBrain wird ein Modell des P-Glykoprotein-Transporters erstellen, der sich in den Endothelzellmembranen der Blut-Hirn-Schranke befindet und Wirkstoffe aus dem Gehirn entfernt. Von der Simulation der molekularen Dynamik dieses Transporters mittels verschiedener Substrate und Inhibitoren erhofft sich das Forschungsteam Erkenntnisse über den der Selektivität der Blut-Hirn-Schranke zugrunde liegenden Mechanismus. Die Ergebnisse des Projekts bedeuten nicht nur solides Grundlagenwissen, sondern werden auch der Entwicklung einer nächsten Generation von Modulatoren für das Zentralnervensystem den Weg bereiten.
Ziel
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.
Wissenschaftliches Gebiet
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
8000 Aarhus C
Dänemark