CONCEPT AND OBJECTIVES
The NEUROMODEL network is going to address the three most important bottlenecks for finding more effective medicine in brain disorders. Those are: (i) identification and validation of pre-symptomatic and surrogate marker for disease progression, (ii) Development of model systems that translate to human pathology and are predictive of clinical efficacy, and (iii) better understanding of disease mechanisms leading to better target selection. Therefore, we have assembled a unique consortium to which industry (5 partners) and academia (5 partners) contribute equally. Through putting together these partners into one network Neuromodel is going to achieve both organization of an excellent training program and performance of excellent research projects with a pronounced focus on intersectional transfer of knowledge. The gain for individual early stage researchers as well as for the participating research teams is obvious. On the one hand, the career chances of young researchers will improve enormously by receiving high quality training (for and by research) in areas of high demand on the employment market. On the other hand, the intersectional, interconnected and integrated research effort pursued by Neuromodel will definitively contribute towards finding more effective treatments in PD and HD. Expertise available within the consortium has lead to the definition of four structural elements – (i) understanding disease mechanisms leading to target identification, (ii) approaches towards treatment, (iii) development of models predictive for efficacy and translating to human pathology, (iv) behavioural markers of animal models - that determines the training as well as the research program.
NEUROMODEL will focus on two neurodegenerative diseases, Parkinson’s and Huntington’s disease, for specific reasons. As for most neurodegenerative diseases, protofibril formation and protein aggregates in form of Lewy bodies in PD and of nuclear inclusion bodies and cytoplasmic aggregates in HD are a general neuropathological feature. Impaired protein degradation, aberrant proteolytic digest of the disease protein, oxidative and nitrosative stress, excitotoxic insult, mitochondrial dysfunction, altered metal homeostasis, failure of axonal and dendritic transport processes, synaptic failure and many other potential pathomechanisms have been proposed to be causative for HD and PD, respectively. In HD and PD, toxic models have previously been used to understand pathophysiology and for preclinical trials (MPTP and 6-OHDA model for PD, and malonate and 3-nitropropionic acid for HD), which were certainly suboptimal to address these questions. The new transgenic and knock-in disease models being developed for HD (Mangiarini et al. 1996; Hodgson et al. 1999; Lin et al. 2001; von Hörsten et al. 2003) and PD (Masliah et al. 2000; Kahle et al. 2001; Nuber et al. 2008) now allow mechanistic pathways to be more specifically deciphered. Also, because, these models more closely reflect the progression of the human condition, the readouts of preclinical treatment studies are more relevant for predicting the outcome of treatment trials in humans. For PD, L-Dopa treatment has existed for nearly 40 years, novel innovative treatments are sparse and a cure is far from in sight. Even for the monogenic HD, the difficulty of drug discovery in terms of translating knowledge into the clinical arena could not have been predicted. Problems have been encountered at several stages, e.g. a focus on specific read outs, poor quality cell culture models for drug screening and the requirement for promising compounds to cross the blood brain barrier. In particular, preclinical assessments have rarely been conducted using rigorously standardized protocols that have sufficient statistical power with the result that positive outcomes can rarely be reproduced between laboratories or across models. Thus, this project addresses many of the limitations of current studies and aims to teach our future generation of scientists how to overcome these limitations.
It is the scientific objective of NEUROMODEL to concentrate on
- In-depth analysis of disease pathways to decipher novel therapeutic targets such as posttranslational modification of disease gene products,
- Target validation and characterization of novel pharmacological targets,
- Studying disease modifiers in vivo by the analysis of specific interactors,
- Generating novel mouse and rat models using lentiviral vectors which can be used more flexible for modifier and therapeutic studies for instance using RNA interference, and
- Standardization of models and technological development of sophisticated animal cages to predict early phenotypes and markers in pre-clinical trials.
Building on the expertise gathered in the NEUROMODEL network, it is also the objective of NEUROMODEL to train young researchers to be fully prepared to meet the increasingly demands for multiple skills of the European (scientific) labour market. NEUROMODEL will implement a comprehensive training programme that is composed of four levels:
- academic and industrial training,
- training in scientific and complementary skills,
- local and network wide European training,
- scientific in-depth training focussed on a specific topic of a PhD thesis and broad spectrum training covering the various sub-disciplines of translational research