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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.

Field of science

  • /medical and health sciences/basic medicine/neurology/stroke
  • /social sciences/social and economic geography/transport

Call for proposal

ERC-2011-ADG_20110310
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant
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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)

UPPSALA UNIVERSITET
Sweden
EU contribution
€ 2 435 327
Address
Von Kraemers Alle 4
751 05 Uppsala
Activity type
Higher or Secondary Education Establishments
Principal investigator
Björn Christer Betsholtz (Prof.)
Administrative Contact
Birgitta Gustafsson (Mrs.)
KAROLINSKA INSTITUTET

Participation ended

Sweden
EU contribution
€ 64 100
Address
Nobels Vag 5
17177 Stockholm
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Jill Blomstrand