Ziel
To elucidate the processes involved in neural development, neural degeneration and regeneration in the central nervous system.
An understanding of the molecular basis of axonal growth and guidance and synaptic plasticity both during normal development and in relation to brain disease is an important issue in developmental neurobiology, clinical neurology and neural pathology. The research is focusing on these processes with special emphasis on selective growth factors, neural transmitters, glycoconjugates and cell adhesion molecules.
A series of relevant methodologies has been established. These include various neural and glial cell cultures, survival assays, carbohydrate chemistry, neurite extension assays, measurement of intracellular calcium and image analysis of cell morphology and motility. The understanding of the roles of neural adhesion molecules has increased significantly. Several important aspects of signal transduction in relation to axon extension is now clarified. The role of neuron cell adhesion molecule (NCAM) in relation to synaptic plasticity is better elucidated and the importance of various growth factors and neurotransmitters in relation to development and degeneration has been evaluated.
During neurodevelopment controlled interactions between neurons and glial cells are of paramount importance. Establishment of neural networks requires growth factors which may be secreted from both glial and neuronal cells and which stimulate growth and differentiation of other cells. Furthermore, adhesion molecules present on the cell surface or secreted into the extracellular matrix assist in the regulation of cell migration and neurite outgrowth. During adult life, degenerative processes may disrupt neural networks. However, even aged brain has a capacity for regeneration to a certain extent. The molecular mechanisms involved in neurodevelopment may be reactivated in regenerative processes. The purpose of this project is to elucidate the influence of growth factors, cell adhesion molecules and proteoglycans on interactions between neurons and glial cells during development, aging and regeneration. Furthermore, signal pathways between neuronal stimulation and neuronal response are to be studied. In brain, nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) are of importance not only for growth and differentiation but also for sustained survival of neural cells. The interaction between these growth factors and the excitotoxic neurotransmittor glutamate which is believed to be involved in neuronal cell death during aging will be investigated in in vitro cell culture systems. Growth of neuronal processes may not only be stimulated by growth factors. Cell adhesion molecules and proteoglycans are likewise involved in dendritic and axonal growth. The mechanism responsible for the dendrite promoting effect of proteoglycans and glycosaminoglycans will be studied at the molecular level. Furthermore, the importance of the neural cell adhesion molecules, NCAM, L1 and N-cadherin, for interactions between neurons and glia will be investigated. NCAM is a highly complex molecule due to alternative splicing and differential glycosylation. Regulation of NCAM function via alternative exon usage and the effect on posttranslational processing will be studied. Finally, the second messenger systems involved in NCAM function will be elucidated. The project will establish a strong european network of scientists working on different important aspects of neurobiology. During the project in vitro systems for evaluation of neurotoxicity will be developed. Furthermore, the project will contribute to the understanding of neurodevelopment and neurodegeneration, hopefully providing a basis for further research into pathological processes in brain.
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2200 COPENHAGEN N
Dänemark