Control of the blood-brain barrier integrity during seizures via the ATP-gated P2X7 receptor

Projektinformationen

EpiBarrier

ID Finanzhilfevereinbarung: 796600

DOI

10.3030/796600

Projekt abgeschlossen

EK-Unterschriftsdatum 19 März 2018

Startdatum 1 April 2018

Enddatum 31 März 2020

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 175 866,00

EU-Beitrag

€ 175 866,00

Koordiniert durch

ROYAL COLLEGE OF SURGEONS IN IRELAND
Ireland

Periodic Reporting for period 1 - EpiBarrier (Control of the blood-brain barrier integrity during seizures via the ATP-gated P2X7 receptor)

Berichtszeitraum: 2018-04-01 bis 2020-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

EpiBarrier is focused on the study of epilepsy, a chronic neurological disease, that affects approximately 65 million people worldwide. Major challenges in epilepsy include social disadvantages, an increased risk for early mortality, and accompanying co-morbidities such as depression and anxiety. Currently, there are more than 25 drugs that suppress seizures, but they have little effect on epileptogenesis, the process leading to a reduced seizure threshold after transient brain insults. Therefore, there is an urgent need to develop new treatments targeting disease progression, based on a non-classical mechanism of action.
In the last decades, special emphasis has been given to the dysfunction of cerebral vasculature and inflammatory processes as important players in epilepsy development, with particular attention on changes in the blood-brain barrier (BBB) functionality. The main objective of this project is to test whether P2X7 receptor signalling contributes to BBB opening during seizures and established epilepsy and whether P2X7 receptor inhibition ameliorates BBB disruption, thereby reducing seizure severity and the development of epilepsy.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

EpiBarrier project is organised into six Work Packages (WPs): WP1,2,3 are the research WP, WP4 refers to Management, WP5 to Communication, Dissemination and Exploitation (WP5) and WP6 to Training/Transfer of Knowledge (WP6).
Through research WPs 1,2,3 the Fellow has determined how P2X7 impacts on BBB integrity during seizures and which genes are regulated by the P2X7 receptor. During the project, the Fellow was training in several state-of-the-art techniques, including modelling an experimental mice model of epilepsy (Traumatic Brain Injury by Controlled Cortical Impact; 1-month secondment in Germany), microarray assays, brain microvessels isolation and differentiation of human-induced pluripotent stem cells.
In WP5, the Fellow communicated project outcomes via posters and oral presentations at 9 National and International conferences. She also took part in 3 public outreach activities to popularize the EpiBarrier project and communicate findings to the general public. The Fellow also participated as a charity volunteer to gain support for epilepsy patients and families in Ireland. In WP6, for researcher Training/Transfer of Knowledge, the Fellow has acquired transferable skills attending at 7 intensive training workshops and multi-day conferences. She conducted 3 workshops with hand-on experience for researchers and provided supervision and mentoring for early career researchers and undergraduate students. The impact of this MSCA-IF is further highlighted through publishing two Open Access peer-reviewed articles in high impact journals, two articles under review, one article submitted, and one article under preparation. The results obtained during this MSCA will enhance several publications in the coming years, in addition to the ones produced and published during the fellowship itself and from new collaborations with different institutions.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Drug-resistant epilepsy affects between 28% and 37% of people with epilepsy. At over €15.5 billion/year in Europe, the healthcare and societal costs of epilepsy are amongst the highest for brain diseases, and the market for epilepsy treatment is estimated at €6.8 billion/year. Critically, currently available treatments act to control and suppress seizures but have no impact on the underlying causes of the disease. Leakage of the blood-brain barrier is one of the earliest pathophysiological disturbances following status epilepticus and may play an important role in the development of epilepsy. Moreover, the promising effects of P2X7 antagonists on epilepsy and the vast investment in current P2X7-related drug development programs point to P2X7 as an ideal therapeutic target in epilepsy. Importantly, the identification of the P2X7 receptor as a regulator of the BBB opening during seizures could impact on other research fields whereby P2X7 activation could be used as a temporary and reversible permeabilizer of the blood-brain barrier, facilitating drug delivery into the brain. Altogether, results from this MSCA-IF have pushed the frontiers of neuroscience forward and have the potential to make a major contribution to highlight the pharmacological manipulation of the P2X7 receptor towards clinical trials.

BNA conference 2019, Dublin, Ireland

1st European Purine meeting 2019, Santiago de Compostela, Spain

Secondment in Walther-Straub-Institut für Pharmakolgie und Toxikologie (Munich)