Brain-derived neurotrophic factor (BDNF) has been initially regarded as a growth factor, but a broader function is suggested by the observation that BDNF is anterogradly transported, released in an activity-dependent manner, and elicits rapid synaptic responses. The host laboratory has demonstrated that BDNF controls the expression of the dopamine D3 receptor (D3R) that various pharmacological and neuro-anatomical data have suggested to be implicated in drug addiction, Parkinson's disease and schizophrenia. Moreover, BDNF-dependent up-regulation of the D3R triggers behavioural sensitisation, a cardinal process in compulsive drug consumption in drug addicts, in dyskinesia in patients with Parkinson's disease, and in psychotic symptoms exacerbation in schizophrenia.
The objective of this proposal is to define and characterize the functions of BDNF as an extra-cellular transmitter. For this, we will characterize BDNF-regulated genes, which, like the D3R gene, may be important for the three disorders, by exploiting data of using high-throughput transcriptome analysis with DNA micro-arrays and design a selective BDNF antagonist. We will also engineer transgenic mice over-expressing BDNF in selected neurons to mimic BDNF over-expression that we observed in animal models of drug addiction, Parkinson's disease and schizophrenia.
The major possible outcomes of this project are likely to enhance our understanding of the pathophysiology of drug addiction, Parkinson's disease and schizophrenia and provide new therapeutic approaches. For this scientific programme, an IRG is requested for reintegration in Europe of an experienced female researcher, initially trained in France, then for 6 years in the US, where she was nominated Research Assistant Professor and developed various experimental approaches needed for the project. She will head a small research unit including 2 students and 1 engineer.
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