The major aim of our research efforts is to investigate the role of glial cells as potential cellular targets for developing novel therapies in human neurological disorders.
Prof. dr. E.M.A. Aronica, neuropathologist, PI, Department of Pathology, Academic Medical Center, University of Amsterdam
Research program Prof. dr. E.M.A. Aronica:
- Epilepsy
- Inflammation
- Neurodevelopmental disorders
- Brain development and ageing
- Neuroncology
Neuron-glia interactions in health and disease
Recent work on neuro-glial cell physiology has revealed that glial cells are much more actively involved in brain information processing than previously anticipated. This finding has stimulated the novel view that the brain should be viewed as a circuit of interactive neuron and glial cell networks. Despite the solidity of the evidence for glia-neuron signalling many fundamental questions on the basic cellular and molecular aspects of this intriguing partnership still remain unanswered or have not been addressed in the functional in vivo context. The major aim of our research efforts is to investigate the role of glial cells as potential cellular targets for developing novel therapies in human neurological disorders. To achieve this aim we use a multidisciplinary approach, creating a collaborative team of specialisms including neurology, neuropathology and neurobiology. In 2006 we performed large-scale studies of gene expression using experimental models and human material from patients with acute and chronic CNS injury. We provided evidence of a prominent and persistent activation of the innate immune response in various neurological disorders with different etiologies, but without a primary inflammatory pathogenesis. This response involves both astrocytes and microglial cells and is associated with the activation of several pathways which influence hyperexcitability, degeneration and regeneration.
In 2007, international collaborations have been established to further investigate the role of astroglial and microglial cells in the initiation and persistence of the inflammatory response associated with neuronal degeneration and hyperexcitability (Grant of the European Union: HEALTH-2007-2.2.1-6:“ Neuron-glia interactions in health and disease”; www.neuroglia.eu ). This has been investigated in human brain and in well established animal models of epilepsy.
In collaboration with the group of Dr. Vezzani (Mario Negri Institute, Italy) we recently reported a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs (Nature Medicine, 16: 413–419, 2010).
We are presently studying the role of proinflammatory signaling-associated microRNAs (miRNA). As described in the recently article published in EJN (Eur J Neurosci.; 31(6):1100-7. 9) we demonstrated in both experimental and human temporal lobe epilepsy the selective up-regulation of the on miR-146a, a microRNA that is induced by pro-inflammatory stimuli, modulating innate immunity through regulation of Toll-like receptor signaling.
New projects starting in 2012:
1. 2012-2015: Grant of the European Union: HEALTH.2011.2.2.2-2 " Pathways common to brain development and ageing: defining strategies for preventive therapy and diagnostics “
Objectives
a. To examine neurodegeneration-related proteins during development: comparing early and postnatal developmental stages in developmental disorders
b. To examine the relationship between neurodegeneration-related proteins and specific developmental pathway.
c. To study selected altered mRNAs, microRNAs and proteins in focal cortical malformations
2. 2012-2016: Characterization of genetic aberrations in pediatric low-grade glioneuronal tumors Stichting Kinderen Kankervrij (KiKa).
The aim of the study is to identify chromosomal changes in an international large series of GNT’s by genomic wide microarray based comparative genomic hybridization (aCGH), PCR and genomic sequencing. During the project these chromosomal changes will be investigated for their potential clinical relevance as related to prognosis, pathogenesis en epileptogenesis. The miRNA profile of GNT’s will be also evaluated. By investigating these biologic characteristics in relation to the clinical data, we can improve the diagnostics and therapy for GNT’s in children, as guided by the clinical biological risk profile of the tumor.