The European Stroke Network A Unique Alliance for Combating Stroke Prof. Dr. Stephen Meairs Department of Neurology University Medicine Mannheim University of Heidelberg, Germany
European Stroke Network 30 Partners from 14 countries
The European Stroke Network European Stroke Research Network (EUSTROKE) Coordinator: Prof. Stephen Meairs Affording Recovery in Stroke (ARISE) Coordinator: Prof. Ulrich Dirnagl www.europeanstrokenetwork.eu
European Stroke Network Launch by European Commission in 2008
Primary Goals decrease the physical, social and economic consequences of stroke on the individual and on society achieve this objective by bringing together European researchers, government, industry, the non-profit sector and patient group associations
Research Themes of ESN Neurovascular Unit Regeneration Reperfusion Brain Immune Interaction / Inflammation Prevention / Neuroprotection
ESN Platforms Clinical Trial Platform (SITS) Stroke Models Imaging Training Patient group interaction (SAFE)
Challenges and opportunities of FP7 research Multidisciplinary Research
Multidisciplinary Research Complex problems demand multidisciplinary approach Utilize the opportunity to integrate researchers new to a particular clinical field Results can be very rewarding Challenge: Requires intensive dialogue and training
Challenges and opportunities of FP7 research Added Value
European Added Value A Tangible Advantage Going beyond research at a national level Cross fertilization of European research centers can lead to better results European cooperation is superior Fresh approaches to a problem provide higher impact Training opportunities, new research impulses Challenge: to stimulate added value in project
Neurovascular Unit
strategies that reduce vascular causes of injury to the brain tissue have been the most successful therapeutic approaches to limiting the extent of injury from ischemic stroke. the microvascular component of the neurovascular unit contributes to neuronal injury
The neurovascular unit circulating blood elements highly specialized endothelial cells pericytes embedded in the endothelial cell basement membrane perivascular antigen presenting cells astrocytic endfeet parenchymal basement membrane neurons
Research focus on NVU little understanding of molecular biology of the NVU interdisciplinary barriers - researchers in the different fields of vascular biology, neurobiology, physiology and cell biology neurons, glia and vascular cells are closely related developmentally, structurally and functionally neurovascular unit highlights the intimate functional relationships between these cells and their coordinated pattern of reaction to injury
New Models for Studying the NVU help identify the cellular and molecular mechanisms involved in NVU maintenance provide a basis for understanding how ischemia leads to breakdown of the NVU understand how the NVU contributes to reperfusion injury
Regeneration
Regeneration and Repair after stroke Molecular and cellular regulation of stroke-induced neurogenesis from endogenous neural stem/progenitor cells. Dynamics of structural recovery of surviving neurons and proliferation of glia cells in relation to axonal growth and expression of molecules involved in trafficking Effects of an antibody against Nogo-A on enhancing functional recovery.
Angiogenesis and vascular stabilization define factors able to induce mobilization from the bone marrow of endothelial and myeloid cell progenitors assess the potential of ex vivo administered vascular progenitor cells in reducing cerebral damage after acute cerebral vessel occlusion define the adhesion molecules and chemokines able to mediate the homing of these cells in the ischemic brain
Angiogenesis and vascular stabilization identify the growth factors which induce angiogenesis in the brain while retaining permeability properties and induce vessel maturation elucidate the optimal interaction of newly growing vessels with pericytes and neural cells identify the bi-directional signals between neural stem cells and brain endothelial cells
Targeted gene therapy and nanotechnology Targeted gene delivery of AAV vectors to the brain with microbubbles and ultrasound Encapsulated biodelivery of SDF1, meteorin, and BDNF for fostering stem cell migration and differentiation using MR-guided focused ultrasound
Transient opening of BBB with focused ultrasound 9,4 Tesla Bruker BioSpec 94/20 USR, rat brain MRI parameters: Insonation characteristics: T1 FLASH Frequency 1 MHz TR: 70 Burst length 10 ms TE: 2 Burst rate 1 Hz ST: 0.5 2.5 MPa L: 16438 W: 32658 1 min insonation time Contrast agent: gadolinium (Gadovist )
Targeted delivery of AAV with focused ultrasound and lipoplex microbubbles Adeno-associated virus - Serotype raav2/1
Triggering regeneration in the brain Non-invasive targeted delivery of brain-derived neurotrophic factor to the brain with focused ultrasound and microbubbles Alexa488-BDNF 4h after ultrasound and microbubbles (BG6895) Rat brain cortex Vessel 80µm 20µm Left image: vessel (neg. for BDNF, left lower corner); multiple neurons staining strongly positive for BNDF (see arrows); punctuate staining possibly due to low uptake of BNDF in cells (not in control hemispheres!) Middle image: high magnification of neurons with very strong uptake of BNDF.
MR-guided Focused Ultrasound
Reperfusion
Neurotoxic effects of thrombolysis Identifying and testing nonneurotoxic thrombolytics Biomarkers to identify individual variability in response to thromboembolic arterial occlusion as well as risk of hemorrhage and neurotoxicity (microparticles)
Adjunct therapies for thrombolysis release tpa PAI-1 tpa activation pln a2-ap inhibition tpa plg pln inhibition Fibrin clot Breakdown FDPs Benchenane et al., Trends In Neurosciences, 2004
23Na concentration related intensity/ tissue vitality (T 2* -weighted 23Na MRI, Acquisition Time = 20min)
Immune Interaction / Inflammation
Inflammation in stroke Identify the efficacy of key anti-inflammatory strategies Determine the effect of systemic inflammation, investigate the mechanisms involved and explore new inflammatory biomarkers Test new inflammatory targets
Brain-immune interactions Explore the basic mechanisms of brain-immune interaction after stroke Establish predictive and sensitive clinical markers to describe the effect of stroke on the immune system
Prevention / Neuroprotection
Prevention of stroke via the NVU effects of functional foods and lipid-lowering drugs on NVU function and susceptibility to ischaemic stroke effects of physical exercise on the physiology of the neurovascular unit investigate whether physical activity and lipid-lowering influence endothelial progenitor cells, thus increasing susceptibility to stroke.
Endogenous neuroprotection Neuroprotective signaling Mechanisms of hypothermia induced neuroprotection Nasopharyngeal human brain cooling
Stroke model platform
Brain imaging platform
Training in stroke models and research
Close Cooperation between Experimental and Clinical Research
The ESN Trials Platform SITS Nils Wahlgren WSO Markku Kaste ESC Michael Hennerici ESO Werner Hacke TRANSLATION ESN Research Clinical Studies
Adapt the SITS network and database to support an ESN TRIALS PLATFORM (data entry and management, data sharing, etc) develop novel data entry procedures suitable for ambulatory use in prehospital settings and for acute phase intervention trials
Cooperation with Stroke Alliance for Europe
SAFE Activity in the ESN Engage in political efforts to foster government and EU funding of stroke research Assist in activities to raise private funds for support of future ESN research Support integration of national stroke research with the ESN to achieve high standards of European research