Community Research and Development Information Service - CORDIS

H2020

BtRAIN Report Summary

Project ID: 675619
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - BtRAIN (Brain barriers training)

Reporting period: 2015-09-01 to 2017-08-31

Summary of the context and overall objectives of the project

In their function to protect the nerve cells in the brain and spinal cord of the central nervous system (CNS) from toxic compounds, the brain barriers also block delivery of drugs to the CNS. This hinders proper diagnosis and effective treatment of many neurological disorders as diverse as Alzheimer’s disease, multiple sclerosis or brain tumors. The blood-brain barrier (BBB) is established by endothelial cells lining the wall of small CNS blood vessels. The blood-cerebrospinal fluid barrier (BCSFB) is established by epithelial cells of the choroid plexus, a structure protruding in the ventricles of the brain and producing the cerebrospinal fluid in which the entire brain is embedded and thus protected from physical impact. The high complexity of these brain barriers has severely hampered progress in the CNS therapeutic market.
The research groups combined in BtRAIN were instrumental in establishing technically advanced procedures for purifying brain barrier cells. They had furthermore developed technologies allowing to i) determine, which genes are expressed by these barrier cells when they mature during embryonic development and to ii) study the signaling pathways involved in barrier maturation. The overall goal of BtRAIN is to combine the different expertises of the BtRAIN beneficiaries to find out, which mechansims are responsible for maintaining integrity of the brain barriers in the adult and how these barriers may change in ageing or during disease. This is of significant importance to understand if dysfunction of the brain barriers contributes to these diseases and also how to deliver drugs across the brain barriers during disease.
To achieve this goal the BtRAIN has two major objectives. Under Objective 1 BtRAIN beneficiaries and partners create and disseminate novel knowledge on the mechanisms regulating brain barrier function in development, health, ageing and disease. A focus of this work is to employ advanced high throughput technologies, allowing to understand which genes are specifically expressed in these brain barrier cells. The aim is to define a brain barrier signature and to identify target structures for therepies, allowing to deliver drugs into the the CNS.
Under Objective 2 BtRAIN beneficiaries have set out to educate a novel generation of young researchers to think out of the box and to bridge disciplinary interfaces by providing a trans-disciplinary training which will allow this next generation of researchers to work along the complete value creation chain in research and technological development.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

BtRAIN has employed a total of 12 ESRs with a different educational background. 8 ESRs have been educated in the life sciences, 1 ESR has a background in bioengineering, 2 ESRs have studied bioinformatics and one ESR is a chemist. This provides the necessary interdisciplinary background at the level of the beneficiaries and ESRs for successfully pursuing the research projects at hand.
Work under Objective 1 has established tissue culture models of the BBB allowing to predict if a specific drug can cross the BBB in the intact organism. These tissue culture models will now be suitable to mimic disease states of the BBB and investigate how this impacts on drug delivery. Furthermore, BtRAIN has established state-of-the art protocols for purifying brain barrier cells and methodologies allowing to isolate the molecule RNA as a readout for gene expression from these cells. High quality RNA is needed to perform the next-generation high throughput sequence analysis of the RNA molecules. Based on the number of copies found in the BBB one can determine, using modern bioinformatics tools, the precise profile of genes expressed at the brain barriers and their potential importance for regulating BBB specific mechanisms. First comparative screenings have already shown that the BBB in vertebrates (e.g. zebrafish, mouse, rat, human) shares 77 genes, which are specifically expressed in BBB endothelial cells and thus provide a genetic BBB signature. This knowledge is prerequisite to now study how the brain barriers change in ageing and disease. To this end BtRAIN has established methodologies to study gene expression in the brain barriers during ageing and in a number of neurological disorders including Alzheimer’s disease, multiple sclerosis, and brain tumors employing mouse models and using human autopsy tissue. First molecular targets that might have an important role in regulating brain barrier function have been identified and will be explored as potential targets to deliver drugs across the BBB.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

BtRAIN will also develop an online platform designated BBBHub allowing researchers in the field optimal access to transcriptome profiles of the brain barriers published by colleagues world-wide. At present these data are not created in a standard manner and very hard to access in the internet based knowledge platforms. Last but not least BtRAIN also reaches out to develop novel strategies for drug delivery across the BBB. To this end BtRAIN explores, if immune cells that can cross the BBB in their function to protect the CNS of potential infections, can take cargo packed in nanoparticles along on their way across the BBB.
The combination of face-to-face trainings in intense one week- workshops with regular training units in a virtual class room provided by the Open University throughout the year has allowed to establish a BtRAIN corporate identity and a level of communication comparable to a department within one research institution. E-Mails, Skype conferences and phone-calls and WhatsApp groups complement these interactions and allow for rapid advancement of each research project beyond the state-of-the-art as the knowledge within BtRAIN is thus readily accessible for everybody. Additional training of the ESRs in skills such as scientific communication have advanced their abilities in presenting their research to colleagues but also to lay people. This is exemplified by the launching of the ESR outreach activity, the BrainBarriers4You.eu homepage, where the ESRs explain the brain barriers and their research within BtRAIN to the lay public in different languages.

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