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European Drug Initiative on Channels and Transporters (EDICT)

: ..
: 01 2008
: 31 2012
: http://www.edict-project.eu

The aim of the European Drug Initiative on Channels and Transporters (EDICT) is to explore the potential of these membrane proteins as targets for development of future pharmaceuticals. EDICT brings together Europe’s foremost experts in membrane transport and ion channel proteins, including two Nobel Laureates.
The project is set to investigate over 80 proteins, which play important roles in diseases as varied as diabetes, osteoporosis, stomach ulcers and cataracts and neuropsychiatric disorders like epilepsy and depression.
Membrane proteins are essential for regulating biological activities within cells – giving us our sense of sight, the ability to breathe, convert nerve signals into actions and use nutrients for energy. They are ideal targets for development of new treatments.
At the moment, only a few scattered researchers are elucidating the structure-activity relationships of membrane proteins. The EDICT project will overcome that isolation and integrate efforts to develop new pharmaceuticals.

Pathogenesis of type 1 Diabetes - testing the hygiene hypothesis (DIABIMMUNE)

: ,
: 01 2008
: 28 2013
: Small or medium-scale focused research project

Preliminary data indicate that there is a strong association between the incidence of immune-mediated diseases and improving standard of living and hygiene. One of the steepest gradient in standard of living worldwide is present at the border between Russian Karelia and Finland with a sevenfold difference in the gross national product, while Estonia represents a country in rapid transition. These three populations comprise a living laboratory providing a unique possibility to test the hygiene hypothesis in the development of immune-mediated diseases. The incidence of type 1 diabetes (T1D) is six times lower in Russian Karelia than in Finland, whereas there are very limited differences in the frequency of risk HLA genotypes in the background population.
This proposal aims at comparing:
(i) the frequency of beta-cell autoimmunity and other organ-specific autoantibodies;
(ii) the frequency of IgE-specific sensitisation and signs of allergy;
(iii) the frequency of various infections;
(iv) the gut microbial flora; and
(v) dietary intake in young children between the three populations.
The birth cohort arm of the study aims at
(i) delineating the ontogeny of the immune system by using modern tools of functional genomics;
(ii) comparing the functional characteristics of regulatory T cells;

OpenTox - An open source predictive toxicology Framework (OPENTOX)

: 01 2008
: 31 2011
: Small or medium-scale focused research project

The goal of the OpenTox project is to develop a predictive toxicology framework with a unified access to toxicological data, (Q)SAR models and supporting information. It will provide tools for the integration of data from various sources (public and confidential), for the generation and validation of (Q)SAR models, libraries for the development and integration of new (Q)SAR algorithms, and validation routines. OpenTox will attract toxicological experts without (Q)SAR expertise as well as model and algorithm developers. It will move beyond existing attempts to solve individual research issues, by providing a flexible and user friendly framework that integrates existing solutions and new developments.

OpenTox will be relevant for REACH as it gives risk assessors simple access to experimental data, (Q)SAR models and toxicological information that adheres to European and international regulatory requirements. OpenTox will be published as an open source project to allow a critical evaluation of its algorithms, to promote dissemination, and to attract external developers. Facilities for the inclusion of confidential in-house data and for accessing commercial prediction systems will be included. OpenTox will contain high-quality data and (Q)SAR models for chronic, genotoxic and carcinogenic effects.

Neurotransmitter cys-loop receptors: structure, function and disease (NEUROCYPRES)

: 01 2008
: 31 2012

Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimer s and Parkinson s, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function.
A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.

European network for genetic-epidemiological studies: building a method to dissect complex genetic traits, using essential hypertension as a disease model (HYPERGENES)

: 01 2008
: 30 2011
: http://www.hypergenes.eu

The project is focused on the definition of a comprehensive genetic epidemiological model of complex traits like Essential Hypertension (EH) and intermediate phenotypes of hypertension dependent/associated Target Organ Damages (TOD). To identify the common genetic variants relevant for the pathogenesis of EH and TODs, we will perform a Whole Genome Association (WGA) study of 4.000 subjects recruited from historical well-characterized European cohorts. Genotyping will be done with the Illumina Human 1M BeadChip. Well-established multi-variate techniques and innovative genomic analyses through machine learning techniques will be used for the WGA investigations. Using machine learning approach we aim at developing a disease model of EH integrating the available information on EH and TOD with relevant validated pathways and genetic/environmental information to mimic the clinician's recognition pattern of EH/TOD and their causes in an individual patient. Our statistical design is with two samples run in parallel, each with 1,000 cases and 1,000 controls, followed by a replication/joint analysis.
This design is more powerful than replication alone and allows also a formal testing of the potential heterogeneity of findings compared to a single step (one large sample) design. The results represent the source to build a customized and inexpensive genetic diagnostic chip that can be validated in our existing cohorts (n=12,000 subjects). HYPERGENES is in the unique position to propose a ground-breaking project, improving the methodology of genetic epidemiology of chronic complex diseases that have a high prevalence among EU populations. Designing a comprehensive genetic epidemiological model of complex traits will also help us to translate genetic findings into improved diagnostic accuracy and new strategies for early detection, prevention and eventually personalised treatment of a complex trait. The ultimate goal will be to promote the quality of life of EU populations.

Improving diagnoses of mental retardation in children in Central Eastern Europe and Central Asia through genetic characterisation and bioinformatics/-statistics (CHERISH)

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: 01 2009
: 31 2012

Mental retardation (MR) is a highly heterogeneous disorder and is of genetic origin in about 50% of the cases. Despite recent progress in research the causes and the pathophysiology of MR remains obscure. It is essential to investigate this in order to develop future diagnostic and therapeutic strategies. The overall goal of this proposal is to establish an interdisciplinary Eastern Europe and Central Asia (EECA) consortium of experts with a joint programme of activities to generate knowledge about MR and the structure and dynamics of the brain as such. This project will be the first to study in depth the prevalence and incidence of MR in EECA.

The objectives of the CHERISH project are to: - to develop a standardized approach for MR diagnosis through clinical workshops and courses - to create a large data-base of patients with clinically well defined MR, both syndromic and non-syndromic - identify cryptic genomic rearrangements through molecular cytogenetic analysis - sequence MR genes and analyze the molecular epidemiology of MR in Eastern European populations - develop diagnostic tools for recurrent/common mutations - identify new MR genes in X-linked and autosomal recessive forms of the disorder - increase awareness on the possible genetic origin of MR and implications for novel therapeutic strategies The project partners will join forces to create a large collection of samples and a database from MR patients which will be become the reference.

All institutions involved are the referral centers for MR in their respective countries. The molecular studies will be performed in technologically-advanced genetic laboratories. A straightforward outcome of CHERISH will lay the basis for a significant improvement of clinical, educational and industrial developments. The project will contribute to improve the management of MR with the potential to reduce the high health care costs and to improve quality of life of the concerned population.