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Mechanisms of regulation of the blood-brain barrier; towards opening and closing the barrier on demand

Mechanisms of regulation of the blood-brain barrier; towards opening and closing the barrier on demand

Objective

In the bone-enclosed CNS, increased vascular permeability may cause life-threatening tissue swelling, and/or ischemia and inflammation which compromise tissue repair after trauma or stroke. The brain vasculature possesses several unique features collectively named the blood-brain barrier (BBB) in which passive permeability is almost completely abolished and replaced by a complex of specific transport mechanisms. The BBB is necessary to uphold the specific milieu necessary for neuronal function. Whereas breakdown of the BBB is part of many CNS diseases, including stroke, neuroinflammation, trauma and neurodegenerative disorders, its molecular mechanisms and consequences are unclear and debated. Conversely, the intact BBB is a huge obstacle for drug delivery to the brain. Research on the BBB therefore has two seemingly opposing aims: 1) to seal a damaged BBB and protect the brain from toxic blood products, and 2) to open the BBB “on demand” for drug delivery. A major problem in the BBB field has been the lack of in vivo animal models for molecular and functional studies. So far, available in vitro models are not recapitulating the in vivo BBB. Our recent work on mouse models lacking pericytes, a BBB-associated cell type, demonstrates a specific role for pericytes in the development and regulation of the mammalian BBB. These animal models are the first ones showing a general and significant BBB impairment in adulthood, and as such they provide a unique opportunity to address molecular mechanisms of BBB disruption in disease and in drug transport across the BBB. Importantly, the new models and tools that we have developed allow us to search for relevant druggable mechanisms and molecular targets in the BBB. The long-term goals of this proposal are to develop molecular strategies and tools to open and close the BBB “on demand” for drug delivery to the CNS, and to explore the importance and mechanisms of BBB dysfunction in neurodegenerative diseases and stroke.
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Principal Investigator

Björn Christer Betsholtz (Prof.)

Host institution

UPPSALA UNIVERSITET

Address

Von Kraemers Alle 4
751 05 Uppsala

Sweden

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 435 327

Principal Investigator

Björn Christer Betsholtz (Prof.)

Administrative Contact

Birgitta Gustafsson (Mrs.)

Beneficiaries (2)

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UPPSALA UNIVERSITET

Sweden

EU Contribution

€ 2 435 327

KAROLINSKA INSTITUTET

Sweden

EU Contribution

€ 64 100

Project information

Grant agreement ID: 294556

Status

Closed project

  • Start date

    1 August 2012

  • End date

    31 July 2017

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 499 427

  • EU contribution

    € 2 499 427

Hosted by:

UPPSALA UNIVERSITET

Sweden