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Grant
Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2010-ITN | Award Amount: 4.98M | Year: 2011

Virus infections remain a major cause of disease, with dramatic costs in mortality, morbidity, and economic loss worldwide. There is an unmet need for potent antiviral drugs, in particular against viruses with a (\)RNA genome which include many important pathogens of humans and animals. Antiviral drug development requires a detailed understanding of virus replication and effective translation of this knowledge into drug discovery. Europe needs well-trained experts with multidisciplinary skills to advance this field. However, few, if any, European training institutes have the broad know-how required to provide such a comprehensive training programme. The EUVIRNA partnership aims to fill this gap with the proposed EUVIRNA training programme. The EUVIRNA partnership consists of six outstanding European academic partners and four industrial partners (one pharmaceutical R&D company and three SMEs), and an associated partner (SME specialized in education). All EUVIRNA partners are recognized leaders in their field, ensuring state-of-the-art training possibilities, and their skills are highly complementary. Three Visiting Researchers will complement the expertise of the partners. EUVIRNA aims to introduce 18 ESRs and 2 ERs to state-of-the-art knowledge and technology applied in molecular virology and antiviral therapy, with both local and network-wide training activities. Individual research projects, research training workshops and intersectoral secondments will be supplemented with complementary skills courses to improve career development and perspectives. The industrial partners are actively involved in the entire programme, and will furthermore organize a 1-week industry-oriented conference aimed at further bridging the gap between academia and industry. Thus, EUVIRNA offers talented researchers a multidisciplinary and intersectoral training programme and prepares them for a future leading role in European molecular virology research and antiviral dru


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.3.3-1 | Award Amount: 31.38M | Year: 2014

Far from receding, the threats posed by infections with epidemic potential grow ever greater. Although Europe has amongst the best healthcare systems in the world, and also the worlds supreme researchers in this field, we lack co-ordination and linkage between networks that is required to respond fast to new threats. This consortium of consortia will streamline our response, using primary and secondary healthcare to detect cases with pandemic potential and to activate dynamic rapid investigation teams that will deploy shared resources across Europe to mitigate the impact of future pandemics on European health, infrastructure and economic integrity. If funded, PREPARE will transform Europes response to future severe epidemics or pandemics by providing infrastructure, co-ordination and integration of existing clinical research networks, both in community and hospital settings. It represents a new model of collaboration and will provide a one-stop shop for policy makers, public health agencies, regulators and funders of research into pathogens with epidemic potential. It will do this by mounting interepidemic (peace time) patient oriented clinical trials in children and in adults, investigations of the pathogenesis of relevant infectious diseases and facilitate the development of sophisticated state-of-the-art near-patient diagnostics. We will develop pre-emptive solutions to ethical, administrative, regulatory and logistical bottlenecks that prevent a rapid response in the face of new threats. We will provide education and training not only to the members of the network, but also to external opinion leaders, funders and policy makers thereby streamlining our future response. By strengthening and integrating interepidemic research networks, PREPARE will enable the rapid coordinated deployment of Europes elite clinical investigators, resulting in a highly effective response to future outbreaks based on solid scientific advances.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.3.2-3 | Award Amount: 17.07M | Year: 2010

This proposal is for a large scale collaborative project in which we propose both to develop novel microbicides directed against new intracellular targets and to investigate novel combinations of highly active anti-retroviral drugs which may be particularly effective as microbicides. Combinations may enhance efficacy but equally importantly will increase the genetic barrier to the development of resistance. The proposal includes development of both slow release and gel formulations, pharmacokinetic and challenge experiments in macaques as well as human studies including a collaborative study with an EDCTP-funded project to use multiplex and proteomic technologies as well as culture-independent DNA-based analysis of mucosal microbiota to investigate biomarkers and establish a baseline signature from which perturbations can be recognised. This is a large consortium comprising 30 partners from 8 EU countries and from Switzerland, Ukraine, South Africa and the United States.Partners include microbicide developers, IPM and Particle Sciences, and producers, Gilead, Tibotec and Virco. Two SMEs will also participate in RTD aspects. The consortium is multidisciplinary with scientists engaged in basic discovery working with new targets and developing novel chemistry to produce compounds with improved safety and efficacy profiles as well as altered patterns of resistance.


Van der Borght K.,Janssen Infectious Diseases Diagnostics BVBA | Van der Borght K.,Catholic University of Leuven | Verbeke G.,Catholic University of Leuven | Verbeke G.,Hasselt University | van Vlijmen H.,Janssen Infectious Diseases Diagnostics BVBA
BMC Bioinformatics | Year: 2014

Background: Different high-dimensional regression methodologies exist for the selection of variables to predict a continuous variable. To improve the variable selection in case clustered observations are present in the training data, an extension towards mixed-effects modeling (MM) is requested, but may not always be straightforward to implement.In this article, we developed such a MM extension (GA-MM-MMI) for the automated variable selection by a linear regression based genetic algorithm (GA) using multi-model inference (MMI). We exemplify our approach by training a linear regression model for prediction of resistance to the integrase inhibitor Raltegravir (RAL) on a genotype-phenotype database, with many integrase mutations as candidate covariates. The genotype-phenotype pairs in this database were derived from a limited number of subjects, with presence of multiple data points from the same subject, and with an intra-class correlation of 0.92.Results: In generation of the RAL model, we took computational efficiency into account by optimizing the GA parameters one by one, and by using tournament selection. To derive the main GA parameters we used 3 times 5-fold cross-validation. The number of integrase mutations to be used as covariates in the mixed effects models was 25 (chrom.size). A GA solution was found when R2 MM > 0.95 (goal.fitness). We tested three different MMI approaches to combine the results of 100 GA solutions into one GA-MM-MMI model. When evaluating the GA-MM-MMI performance on two unseen data sets, a more parsimonious and interpretable model was found (GA-MM-MMI TOP18: mixed-effects model containing the 18 most prevalent mutations in the GA solutions, refitted on the training data) with better predictive accuracy (R2) in comparison to GA-ordinary least squares (GA-OLS) and Least Absolute Shrinkage and Selection Operator (LASSO).Conclusions: We have demonstrated improved performance when using GA-MM-MMI for selection of mutations on a genotype-phenotype data set. As we largely automated setting the GA parameters, the method should be applicable on similar datasets with clustered observations. © 2014 Van der Borght et al.; licensee BioMed Central Ltd. Source


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.3.2-1 | Award Amount: 3.90M | Year: 2008

Standard therapy of infection with the human immunodeficiency virus type 1 (HIV-1) is based on potent cocktails of drugs targeting viral proteins. This treatment is associated with severe side effects and is almost unaffordable for the patients living in sub-Saharan Africa. Incomplete suppression of HIV replication results in drug-resistance. Therefore, a continued research effort is required to develop more potent, cheaper and less toxic antivirals. The insight has grown that HIV requires cellular proteins to serve as co-factors for viral replication. Our over-all objective is to develop novel drugs by targeting co-factors required for HIV replication. The virus will find it difficult to develop antiviral resistance against drugs targeting interaction between invariable cellular proteins and conserved viral protein domains. We will focus on the cellular proteins that mediate HIV trafficking, nuclear import and integration, such as Lens Epithelium Derived Growth Factor (LEDGF/p75), a novel cofactor of HIV-1 integration. THINC is composed of 3 virologists, 2 medicinal chemists, 1 virologist from South Africa, 1 structural biologist, 1 pharmaceutical company. Our first objective is to identify and validate novel co-factors of HIV trafficking, nuclear import and integration as novel targets for anti-HIV therapy. The second objective is to develop new drugs against the validated cellular target LEDGF/p75. The third objective is to perform this work in the perspective of those who will benefit most: the HIV infected people all over the world. The initial steps of target validation and hit identification will mainly be taken by academic groups, while optimization and (pre)clinical development of drugs requires the participation of Tibotec, a European company devoted to the development of antiviral drugs. The project will also increase our generic understanding of protein-protein interactions (PPI).

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