Descrizione del progetto
Modellizzare la barriera emato-encefalica
La barriera emato-encefalica (BBB, Blood–Brain Barrier) è una frontiera altamente selettiva che blocca l’accesso al cervello di agenti patogeni e tossine. Sebbene aiuti a mantenere l’omeostasi cerebrale, impedisce che specifici farmaci per i disturbi del sistema nervoso centrale raggiungano il cervello. Il progetto HumBrain, finanziato dall’UE, realizzerà un modello del trasportatore della glicoproteina P che si trova nelle membrane delle cellule endoteliali della BBB ed espelle i farmaci dal cervello. Attraverso la simulazione della dinamica molecolare di questo trasportatore con vari substrati e inibitori, gli scienziati sperano di comprendere il meccanismo alla base della selettività della BBB. Oltre a fornire conoscenze fondamentali, i risultati del progetto apriranno la strada alla progettazione della prossima generazione di modulatori del sistema nervoso centrale.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
8000 Aarhus C
Danimarca