Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS


NCL-MODELS Streszczenie raportu

Project ID: 503051
Źródło dofinansowania: FP6-LIFESCIHEALTH
Kraj: Finland

Final Report Summary - NCL-MODELS (Dissecting neuronal degeneration: Neuronal ceroid lipofuscinoses from genes to function)

The Neuronal ceroid lipofuscinoses (NCLs) are collectively the most common inherited progressive encephalopathy of childhood. Each form of NCL is characterised by the progressive death of CNS neurons and these rare diseases provide an excellent model to define the molecular events that result in neurodegeneration.

The aim of the NCL-models project was to reveal pathogenic mechanisms in the neuronal ceroid lipofuscinoses. The goal of the project was to carefully characterise the individual NCL proteins towards a further understanding of their normal roles and the molecular mechanisms by which loss of their function leads to neurodegeneration. The data obtained has significant implications for other disorders as well, providing insights into the cellular processes that influence neuronal death and ageing. The project used a multidisciplinary approach, in which a key element was the generation of novel models for NCL.

These models, including cell, yeast, nematode and mouse models were used to study the pathogenic mechanisms of the NCLs by a variety of techniques including molecular genetics, cell biology, mRNA and protein expression profiling, proteomics, and morphological approaches. The combination of top level European NCL scientists facilitated the integration of research capacities across Europe, increasing coherence and providing a critical mass of investigators. This integrated multidisciplinary research program enabled direct interactions between technology and biology and is providing the knowledge base essential for the rational design of therapeutic interventions. Importantly, the NCL-models project organised efficient research training in functional genomics and neurobiology.

In summary, the NCL-models project has efficiently utilised mammalian cell, yeast, nematode and mouse models to characterise the individual NCL proteins and their physiological functions. These new collaborative efforts have resulted in several major achievements in our understanding of NCL neurobiology. Major recent reviews, most of them produced by the participants of NCL-models, summarising current knowledge on the NCLs have been published.

The ultimate impact of the NCL-models project is in providing the basis for therapeutic approaches for these progressive, fatal neurodegenerative disorders of childhood. The entire NCL-models network aims at improving the health of NCL patients and quality of life for families affected by this major paediatric neurodegenerative disease.

The NCL-models project has significantly added to our knowledge of the function of the NCL proteins, the mechanisms of neurodegeneration and the disturbed metabolic pathways underlying each form of NCL by:
1) providing comprehensive and uniform analysis of the neuronal metabolism and interactions of NCL proteins;
2) development of novel yeast, nematode and mouse models of NCL;
3) performing a systematic analysis of NCL model organisms using modern morphological methods, as well as genome-wide strategies for gene and protein expression combined with novel bioinformatic analysis tools.

This project has led to better understanding of the maintenance of the nervous system, and provided the knowledge base for designing therapy, and essential tools for evaluating subsequent therapeutic approaches. Furthermore, resolving the mechanisms of neurodegeneration in the NCLs is likely to have a broader significance for understanding the causes of neuronal death in other neurodegenerative diseases, thus having impact beyond this group of rare NCL disorders.

Research training was an extremely important part of this multidisciplinary programme and one central task was to organise and monitor the research training of young scientists studying functional genomics and neurobiology. Exchange of these junior investigators between laboratories helped to provide them with a thorough training in a range of different techniques. This exchange of young scientists between laboratories of the collaborative network greatly facilitated achieving the research goals of this NCL-models project. More importantly, it has helped to create an active and collaborating scientific network which will continue far beyond this project.

The NCL-models project has utilised the genome-wide approaches provided by the Human Genome Project to dissect the specific disease mechanisms that operate in the NCLs. The combination of top level European NCL scientists facilitated the integration of research capacities across Europe, increasing coherence and providing a critical mass of investigators. This integrated multidisciplinary research has enabled direct interactions between technology and biology which is especially important in the translation of genomic data into practical applications. The economic development and impact produced by these research achievements is on-going, but the data we have gathered may ultimately influence, initiate or enhance therapeutic activities and form the basis of clinical trials. The economic benefits will not only be for the manufacturers of these therapeutic regimens but via lowering disease costs incurred by NCL patients and their families.

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