Project: Role of danger signals in stroke and therapeutic targeting by nanobodies

Stroke kills more than 500,000 people each year in the European Union alone and is also the leading cause of permanent disability. Due to the demographic age shift these numbers will increase continuously. The current treatment (thrombolysis with tPA) has a very limited time window (usually less than 4.5 hours) for application. Based on the observation that the damaged brain tissue triggers an immediate inflammatory reaction, we propose that interfering with the activation of this inflammatory cascade will be beneficial. Danger molecules are the first signals released from dying tissue after stroke. These danger signals bind to receptors on immune cells that will result in their activation and the release of inflammatory and neurotoxic mediators, resulting in amplification of the immune response and subsequent enlargement of the damaged brain volume. The release of danger signals is a central event that leads to a multitude of signals and cascades in the affected and neighbouring tissue, therefore, providing a perfect target for therapy. Nanobodies are truncated versions of the bulky antibody molecules, offering advantages such as better reach of the target tissue, easier administration, lower toxicity, low costs, and easiness of production. We, therefore, have generated nanobodies specific for blocking danger receptors that have been successfully tested in cell culture and animal models. With this project, we aim to understand the role of danger signals and their receptors in stroke and we plan to use nanobodies for treatment in mouse models of stroke. Last, we will assess the role and function of danger receptors in cultured human cells subjected to strokelike conditions and in brain sections from stroke patients.

Acronym	NanoStroke
Duration	01/04/2012 - 31/12/2015
Network	NEURON
Call	NEURON-2011 Cerebrovascular Diseases

Project partner

Number	Name	Role	Country
1	University Medical Center Hamburg-Eppendorf	Coordinator	Germany
2	University of Würzburg	Partner	Germany
3	IRCCS San Raffaele Pisana	Partner	Italy
4	Universidad del País Vasco	Partner	Spain
5	Instituto de Investigaciones Biomédicas de Barcelona	Partner	Spain