Work Packages
WP1
Activity: Management
Partner no: 1, 2
Objective: Provide effective management to the project.
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WP2
Activity: RTD/Innovation
Partner no: 14, 15
Objective: The WP will establish an ethics committee to provide a clear system of supervision of individual workpackages within the project.
An extensive review of literature dealing with ethical, social and legal aspects of genetic testing in children will be carried out.
Empirical research in the preferences and needs of target populations toward genetic testing on asthma susceptibility will be carried out.
The WP will formulate and provide policies for the conduct of genetic testing in children in this study and for the generation and handling of data from questionnaires, biological samples and test results.
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WP3
Activity: RTD/Innovation
Partner no: 1, 2, 3, 5, 7, 10, 25, 26, 28, 32
Objective: The WP will examine cross-sectional and cohort studies of asthma in the European population.
The study will investigate all the most common forms of asthma and the key events in the natural history of asthma at different times of life.
The study will contain detailed measurements of all known major environmental factors influencing asthma. A detailed description of the investigation of novel environmental factors will follow in WP6.
Genotyping will be carried out of all known asthma genes, all genes potentially interacting with the environment such as microbial exposure, smoking, air pollution etc, and novel genes identified by a whole-genome association study.
Genotypic data will be analysed for gene-gene and gene-environment interactions. Measurements of risk will be made for gene-gene and gene-environment interactions. The public health implications of these findings will be considered.
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WP4.1
Activity: RTD/Innovation
Partner no: 2, 7, 8, 22
Objective: To perform the field work to recruit asthmatics and controls among farmers and non-farmers in rural alpine regions and South-West Poland.
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WP4.2
Activity: RTD/Innovation
Partner no: 1
Objective: The study will investigate genetic and environmental determinants of severe asthma in adults and children attending tertiary referral clinics.
The study will establish a cell, tissue and fluid bank as a resource for genomic and proteomic studies outlined in 4.1.5 (WP5) below.
Environmental factors to be studied will include parental smoking and the microbial flora of the airways.
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WP4.3
Activity: RTD/Innovation
Partner no: 2
Objective: The WP will recruit a clinically selected case control population for genetic studies of childhood asthma in central Europe, as a reagent for WP5.2.
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WP5.1
Activity: RTD/Innovation
Partner no: 3
Objective: The WP will type 1500 SNPs using a single Illumina bundle on approximately 10,000 case-control samples from WP3 (Phase II genotyping).
SNPs will be identified through a whole-genome association study (WP5.2), and through a list of all known or putative asthma genes, genes involved in innate immunity and genes that interact with microbia, allergens and cigarette smoke.
Unlinked non-disease SNPs will be included, in order to quantify the genetic structure of the European population.
Verified genetic effects will then be typed in a Phase III study of large cohorts.
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WP5.2
Activity: RTD/Innovation
Partner no: 3, 12, 29, 30, 31
Objective: The WP will carry out a whole-genome association study with 350,000 SNPs, using the gene-centric whole-genome and the Hapmap phase I panels developed by Illumina.
750 cases and 750 controls of children with asthma will be studied.
The results will be integrated with a Wellcome-Trust funded whole genome-association study of 1500 subjects in families with children with severe asthma to be carried out by Partner 1.
Confirmation of positive results will be sought in 800 cases and 1000 controls from the Kinderklinik in Munich.
The results will be integrated with findings from the genomics (WP5.5) and proteomics (WP5.3) workpackages.
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WP5.3
Activity: RTD/Innovation
Partner no: 3
Objective: The WP will identify proteins that are differentially expressed in asthmatics and non-asthmatics.
The WP will identify proteins that are differentially expressed in farmers and non-farmers children.
The WP will study plasma, saliva, and broncho-alveloar lavage.
Proteins found to be of diagnostic interest will be developed for high-throughput assays by the JRC.
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WP5.4
Activity: RTD/Innovation
Partner no: 4, 21
Objective: To carry out a joint analysis of all the genetic epidemiology studies in the European genealogical context.
To develop a robust statistical approach to the analyses of highly dimensional data from whole-genome association and DNA microarray experiments. To develop straightforward methods to analyze gene-gene and gene-environment interaction.
To develop forecasting methods to predict the risk of asthma, based on the knowledge of genetic and environmental risk factors provided by the above methods.
To integrate genetic and genomic findings with bioinformatic interpretation of public and consortium databases.
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WP5.5
Activity: RTD/Innovation
Partner no: 1
Objective: The WP will generate a database of expression data from asthmatics and non-asthmatics.
Expression studies will be carried out of primary airway epithelial cells from asthmatics and non-asthmatics.
Expression studies will be carried out on EBV transformed cells from peripheral blood of adults and children with severe asthma and controls.
Expression studies will be carried out on resting cells cultured and harvested under standard conditions, and these results compared to cells subjected to particular pro-inflammatory or environmental stimuli described in WP7.
Genomic studies will also be used as a systematic tool to classify and identify the microbial flora from environmental samples, from the upper airways of asthmatic and normal children, and from broncho-alveolar lavage of children with severe asthma and controls.
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WP6.1
Activity: RTD/Innovation
Partner no: 11, 17, 18, 19, 20
Objective: To generate a data bank with environmental information from all study subjects providing DNA samples from existing populations.
To validate the assessment of microbial exposures in dust samples.
To validate the assessment of various components of farm milk samples.
To assess microbial and milk component exposures of rural populations in alpine regions and South-West Poland.
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WP6.2
Activity: RTD/Innovation
Partner no: 20
Objective: The WP will quantify the effects of active and passive cigarette smoke in the populations described in WP3 above.
The WP will identify interactions between specific asthma genes and environmental tobacco smoke in utero and in early childhood as well as in adulthood. The effect of gender will be assessed on these interactions.
Interactions will also be sought between tobacco smoke and other environmental factors, such as industrial exposures quantified from WP6.3.
These findings from the WP will be translated to functional genomic research using appropriate models in WP7.
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WP6.3
Activity: RTD/Innovation
Partner no: 25
Objective: The WP will examine gene-environment interactions in cases and controls with industrial asthma.
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WP6.4
Activity: RTD/Innovation
Partner no: 6
Objective: To fractionate and structurally finger print dust samples from asthma protective and non protective environments.
To provide fractionated samples for biological screening and immunological in vitro tests described in WP7.
To purify immune-modulatory molecules from active fractions.
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WP7.1
Activity: RTD/Innovation
Partner no: 1
Objective: The WP will investigate the effects of environmental agents on airway epithelial cells in a standardised model that tests the response of epithelial cells to inflammatory stimuli.
Initially, the effects of IL-1 and LPS stimulation in the presence and absence of cigarette smoke will be examined. Agents identified in WP6 will subsequently be tested.
The model will be used to investigate the effects of target genes by knockdown with RNA interference.
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WP7.2
Activity: RTD/Innovation
Partner no: 13
Objective: To investigate the effects of environmental agents on dendritic cells (DCs).
To investigate the effect of environmental factors on the induction of TH1, TH2 and Treg cells by DCs.
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WP7.3
Activity: RTD/Innovation
Partner no: 16, 20
Objective: To investigate the effects of environmental factors on airway hyperresponsiveness, airway inflammation and sensitization in murine models of asthma.
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WP8.1
Activity: RTD/Innovation
Partner no: 24
Objective: The WP will develop Immunochemicals for investigation of innate and adaptive immune responses.
The WP will initially develop activators and antagonists for Toll-like receptors.
As new therapeutic targets are defined in WP5 and WP7, this WP will develop overlapping peptides and other methods for mapping of the functional regions of target proteins, and for their structural investigation and post-translational modification.
The WP will subsequently develop cell-permeable peptides as novel therapeutic compounds, with and without covalent coupling to blockers of signal transduction.
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WP8.2
Activity: RTD/Innovation
Partner no: 23
Objective: The WP will establish the use of genetic polymorphisms and other biomarkers to guide the therapy of asthma.
The WP will utilise unique access to the Finnish population, associated medical records, detailed clinical diagnostic data, outcomes data and genealogy records.
The WP will validate and commercialize biomarkers from WP3, WP5 and WP7 for use in drug development, molecular diagnostics and improved patient care.
WP8.3
Activity: RTD/Innovation
Partner no: 27
Objective: The WP will develop novel biotherapeutics for the treatment of asthma.
A target will be selected in the second year of the study, from the results of WP3 and WP5.
Antibodies will be used as therapeutic compounds in model systems developed in WP7.
An SME partner or partners will be identified to carry out the work.
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WP9
Activity: RTD/Innovation
Partner no: 1, 2, 3, 13, 20, 21, 22
Objective: The WP will provide opportunities for promising young scientists to train in leading European centres, primarily through a studentship program.
The WP will establish cross-disciplinary links between different groups with complimentary expertise, primarily through a program of visiting fellowships, and through workshops.
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EU Cordis University of Munich Imperial College London
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© GABRIEL 2006. All rights reserved. Website contact: Dana Finch d.finch@imperial.ac.uk Updated January 2007
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