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Grant
Agency: Cordis | Branch: FP7 | Program: MC-IIF | Phase: FP7-PEOPLE-2010-IIF | Award Amount: 181.08K | Year: 2012

Transcription factors (TFs) are capable to identify their target sites on DNA in a extremely efficient fashion. The observation that a simple 3D diffusion search cannot account for such efficient targeting has led to different mechanisms to be proposed in the last decades, including compact exploration induced by facilitated diffusion (i.e. combination of 1D sliding and 3D diffusion) or by fractal-like chromatin structure. Despite the evidence for 1D sliding of TFs on DNA and for fractal nuclear organization, it still needs to be demonstrated that these phenomena play a significant role in the TF search mechanism in a living cell. Fluorescence microscopy and in particular single molecule tracking (SMT) provides an excellent tool to investigate the kinetics of proteins in living samples. SMT has mostly been applied to in-vitro and in-membrane environments due to limitations associated to prolonged 3D tracking. In this project we plan to overcome the limitations associated to 3D SMT and to apply the developed technology to investigate the in-vivo search mechanisms of p53, an important TF, involved in the determination of the cell fate under stress conditions. We aim to quantify the role of compact exploration in p53 targeting in living cells, and by the analysis of mutated p53 how 1D sliding affects such phenomenon. Furthermore, we plan to identify the changes in the p53-DNA association and in the p53 search after induction of cell stress by DNA damage. Summarizing, the project aims to strongly improve current methods for tracking individual molecules in 3D and to advance our knowledge about the mechanisms of TF targeting.


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.


The development of innovative Advanced Therapies offers new approaches to tackle major diseases such as cancer, diabetes, Alzheimer or Parkinson. The progress made in the fields of Tissue Engineering and Regenerative Medicine (TERM) promises to deliver long awaited new solutions. They are recognized as potential sources for medical progress and significant economic growth where Europe should position itself. Since advanced therapies are often based on personalized medicine, the translation of medical developments into real-life, sustainable therapies is challenged by several hurtles. We need new scientific (multi-disciplinary, GMP-conform research environment), economic (new business models for high-cost-low frequency treatments) and structural (translation-oriented RTD) solutions. Europe has to improve its research capacities and accelerate translation to catch up with the US and keep ahead of rapidly developing Asian countries. TERM project aims at a consolidating skills and infrastructures among European regions and their research clusters through the definition of joint actions and mentoring. The goal is to derive high potential, translation-oriented projects from joining skill-sets, infrastructures and networks and from recognizing the requirements of the market forces. The financing situation shall also be analyzed and adapted to the requirements. TERM project will develop knowledge and strategies on how to use resources of the regions and clusters more efficiently with more synergy and focus. The knowledge generated shall be used to develop tools to efficiently assess the research potential of a region, implement best practices in a research cluster, develop inter-regional programs with joined research goals and suggest financial instruments that support these efforts. Therefore, the output of our project will be the development of a European strategy, action plan and best practice tools on how to link research clusters from different regions


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.1.4-1 | Award Amount: 14.70M | Year: 2010

Preventing immunological rejection of transplanted organs without the need for long-term use of pharmacological immunosuppression is a primary objective in transplantation medicine. Reducing the need for immunosuppression would dramatically improve the outcome for transplant recipients and reduce health costs for society. The means to achieve this goal has not been realised with pharmacological or biological agents yet. Conditioning the immune response of solid organ transplant recipients towards allograft acceptance using cell-based therapies is now becoming technically feasible and clinically promising. The central focus of our proposed cooperative work programme is to produce distinct populations of haematopoietic regulatory cells and comparatively test their safety and efficacy in minimising pharmacological immunosuppression in solid organ transplantation. Preparations of regulatory T cells, macrophages and dendritic cells will be licensed for clinical manufacture in outstanding research facilities across Europe, and subsequently, these different tolerance-promoting cell types will be assessed in a single Phase I/II clinical study for safety, clinical practicality and efficacy. The therapeutic potential of these cells will be directly compared using one, single clinical protocol. In addition, we will study the tolerogenic characteristics of these regulatory cell types at in-depth molecular and functional levels. These integrative, but very focused, research plans are expected to result in the identification of the most promising regulatory cell products for further testing, and commercial exploitation: the final outcome is to identify a cell product which has genuine potential to induce operational tolerance if correctly applied in a Phase IIb clinical trial. This objective can only be accomplished by the cooperation of the most experienced researchers in this field across Europe, in alliance with SMEs devoted to cell therapy.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.4-1 | Award Amount: 9.25M | Year: 2010

Leukodystrophies (LDs) are inherited rare neurodegenerative diseases of the white matter and its main component, the myelin, that are affecting predominantly children. Severity of the disease is related to the axonal dysfunction due to myelin deficiency or destruction. Despite the achievement of remarkable advances made in the past decade, there is no current curative therapy. The development of therapeutic approaches for myelin repair and neuroprotection constitutes the main objective of the LeukoTreat project. Indeed LDs constitute prototypic pathologies to tackle myelin formation/destruction issues as well as glial cells dysfunctions in neurodegeneration. The global aim is to promote the development of therapeutic strategies for the largest number of LD affected patients and further applications to more common white matter disorders and finally neurodegenerative diseases. For this purpose, the project will combine the expertise of (i) recognized European research teams in the field of White Matter diseases (COST Myelinet), (ii) high-technology SMEs, (iii) experts in medical ethics and (iv) LD patients and families associations. To develop efficient therapies, the LeukoTreat project is based on 5 complementary approaches consisting in: (i) collecting information on the epidemiology, the natural history, the genotype/phenotype correlation of LDs for at least 500 patients; (ii) validating/identifying biomarkers for therapeutic decisions/follow up to isolate new therapeutic targets; (iii) developing pharmacological strategies with the ultimate objective to launch at least 4 pharmacological clinical trials during 5 years following the project; (iv) developing innovative gene and cell therapies with the ultimate objective to launch at least 3 clinical trials during the next 5 years; (v) tackling ethical impacts of the proposed therapeutic challenges by integrating the participation of patients driven by a well-experienced research team strongly skilled in ethics

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