H2020Индивидуална стипендия2022–2024

HumBrain · Computational modelling of the human brain lipidome

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2022-03-01 → 2024-02-29
Финансиране от ЕС: 207 312 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Молекулярното моделиране изследва как лекарствата преминават през кръвно-мозъчната бариера и как протеини като P-гликопротеина блокират достъпа им до тумори. Това помага за подобряване на терапията при рак на мозъка и невродегенеративни заболявания като болестта Алцхаймер.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Computational modelling of the human brain lipidome

The HumBrain project addresses the problem of how to improve blood-brain barrier (BBB) penetration of therapeutics for the treatment of central nervous system (CNS) disorders using molecular modelling techniques. In addition, the project probes the role of of a protein in the BBB, the P-glycoprotein efflux pump, which is associated with multidrug resistance to chemotherapeutics in treating glioblastoma, a particularly deadly form of cancer with an extremely low survival rate. The societal importance of the HumBrain project arise from the fact that the number of people living with neurodegenerative disorders are set to double by 2050, with Alzheimer’s disease in particular set to become a public health emergency. Similarly, it is currently very difficult to treat brain cancers, including glioblastomas, in part due to the challenge in achieving significant brain distribution of chemotherapeutics at the tumour site. With this MSC Action we turn to precision medicine with molecular modelling to improve the understanding of the role of the blood-brain barrier in limiting the delivery of therapeutics, as well as how pumps can be regulated to improve the delivery and availability fraction of a chemotherapeutic agent. The overall objectives to HumBrain are: (1) to elucidate P-gp protein modulation by ligands to stop multidrug resistance, as the project sets out to map the P-gp binding site for the substrate rhodamine-123 by MD simulations, and compare this to the mechanism of binding for a promising third generation P-gp efflux inhibitor, tariquidar; (2) to elucidate the P-gp protein dynamics when embedded in a complex membrane at the atomistic and coarse grain levels; and (3) to elucidate CNS penetration mechanism across the blood-brain barrier by calculating the free-energy of partitioning of substrate molecule across the BBB, as well as calculate the interaction of tariquidar with P-gp in the binding site. The conclusion of HumBrain are that we found novel insights into the mechanism by which tariquidar inhibits P-gp, which is crucial to dealing with the problem of multidrug resistance to chemotherapeutics. The MSC Action has thus contributed novel insights to designing methods to improve the delivery of chemotherapeutics to brain cancer patients. We uncovered novel mechanistic insights into how drugs cross the blood-brain barrier using precision medicine computational models.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

AARHUS UNIVERSITET · Aarhus CКоординаторДания