Molecular coding and subset specification of dopamine neurons
generating the meso-limbic and nigro-striatal system
Concept and objectives
Our project is aimed at identifying molecular and physiological mechanisms of the development and maintenance of mesodiencephalic dopaminergic neurons, the neuronal population affected in Parkinson's disease, in affective disorders as schizophrenia and autism, and in anxiety related disorders as depression. The project aims to combine three distinct levels of research, early patterning, differentiation and axon pathfinding. The acquired knowledge will be used to design new strategies to treat the above mentioned patients and provide new leads for drug targeting.
Recent work by the consortium members has led to the proposal of a molecular pathway that leads to the formation of mdDA neurons in a specific region spanning parts of the diencephalon and mesencephalon (reviewed by Smidt and Burbach, 2007). The data has suggested that specific subsets arise in terms of molecular signature and function (reviewed by Smits et al. 2006). Although the overall developmental pathway has been uncovered recently, many questions remain. Therefore, in this proposal we aim to:
In order to achieve this we propose the following key objectives which will be handled through the three Workpackages:
1 Ventricular zone programming and early specification of the mdDA neuronal phenotype
2 Mechanisms of migration and guidance of mdDA neurons
3 Genetic programming, terminal differentiation and maintenance
The project relies on a multidisciplinary genomics and molecular biology approach to unravel the fundamental biological process used to generate and maintain proper functioning mdDA neurons.
The “mdDANEURODEV” project is essential for identifying new fundamental data that may lead to the generation of new therapies for diseases such as Schizophrenia, Autism, depression and addiction. All knowledge obtained in this project will be published, patented and shared by the consortium so the results can be quickly exploited by other research groups and companies that can build upon the data generated within the consortium.
Contribution to the programme “2.1.2 Systems biology”
The project accurately fulfills the objectives of Health-2007-188.8.131.52 call Multidisciplinary fundamental genomics and molecular biology approaches to study basic biological processes relevant to health and disease.
Psychiatric diseases and neurodegenerative diseases as Parkinson's have a great impact on our society. With the increase of the complexity of our society and the increase in mean age, diseases that hamper the cognitive function are having more and more impact.
The current treatment paradigms are collectively based on suppressing symptoms. To make the step towards understanding the disease itself and treating the disease and its onset, new experimental data are crucial. Looking at the last decade enormous progress has been made by the consortium members and others to provide new data on molecular players that are involved in the generation and function of the neuronal cell groups that are directly and indirectly involved in the above-mentioned diseases. Also the possibility to generate new mdDA neurons from human ES-cells to be used in a cell replacement paradigm depends on data describing the basic biological process that generates mdDA neurons.
All consortium members are absolute experts in this field and complement each other in order to expand the area of expertise essential to address the multi-disciplinary approach. This generates confidence that the key objectives described can be fulfilled by this consortium. Moreover, the consortium members are certain that the achievements from this project, as presented here, will fulfill the socio-economic need for basic knowledge of complex diseases to generate basic knowledge essential to perform translational biology in the process of the development of novel medication.