Solna, Sweden
Solna, Sweden

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Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: PEOPLE-2007-1-1-ITN | Award Amount: 3.46M | Year: 2009

Eight partners from six different EU countries will converge in NotchIT, a multi-site ITN aimed to increase the knowledge of cellular and molecular mechanisms by which Notch signaling regulates the development and pathology of different tissues. Notch signaling plays a key role in cell-fate determination and differentiation of various cell types and aberrant Notch signaling is associated with pathogenesis of different human diseases, including cancer. NotchIT integrates the research and training activities of the eight different partners, who are all leaders in Notch signaling and related fields, to specifically address three strategic initiatives, which are central to European science and health economy: - the core Notch signaling mechanism with the purpose of constructing a state-of-the-art molecular tool box for Notch signaling and to disseminate this knowledge and reagents at a pan-European level. - the role of Notch signaling in the differentiation and pathology of various cell types with the purpose of using Notch signaling to improve our means to steer stem cell differentiation and to correct aberrant Notch signaling in pathologies. - how Notch signaling can be exogenously controlled through pharmacological approaches, in order to break new ground and to ultimately design new diagnostic and therapeutic protocols. The training component in NotchIT is deeply integrated with the research programme. The partners in NotchIT possess a wide range of expertise and work in operationally diverse environments: Hospitals, Universities, Research Institutes and Industry. This broad knowledge-base, combined with an integrated set of courses, workshops, meetings and cross-laboratory visits, provides an excellent training opportunity for early stage and experienced scientists in the center, and will prepare them for high level positions in academia and industry.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.1-6 | Award Amount: 3.95M | Year: 2008

The co-operative Metafight project will perform functional studies to understand the dissemination and outgrowth of metastasis through systematic analysis of the Core Invasive Machinery contained within integrin-mediated ECM attachment structure. It includes a large and discretely localised intracellular signalling network which drives migration and invasion. Our strategy is based on the hypothesis that metastatic cells arise from molecular changes that alter the primary tumour architecture as well as the tumor microenvironment, by reversible modulation of cell adhesion, onset of signalling pathways and acquisition of novel migratory and invasive capacities. The Metafight Consortium is strengthened by established combined expertise on adhesion receptor signalling and availability of unique tumor cell and cancer animal model systems. We will characterise known and novel components of the Core Invasive Machinery, responsible for development and homing of metastasis, by innovative in vivo non-invasive imaging techniques. The Metafight project comprises seven major interrelated Work Packages (WP). WP1 is designed to investigate the molecular and functional architecture of the Core Invasive Machinery, from which depends tumour cell migration and eventually invasion. WP2 and WP3 screen for key modulators of metastasis formation in in vivo murine models, by non-invasive imaging techniques. WP4 is related to a comprehensive proteomic analysis of expression and phosphorylation of our candidate modulators in metastasis formation. WP1-4 feed into WP5, which builds upon and exploits knowledge generated in the first four WPs and translates it into existing pharmacological interventions to generate new candidate drugs. This will lead to patent filing and licensing strategies. WP6 and WP7 handle dissemination and management activities. The ultimate accomplishment will include improvement of health, reduction of health expenses, as well as creation of new jobs and economic benefit.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.2.1-7 | Award Amount: 4.59M | Year: 2009

MOLPARK aims to define the basic cellular and molecular mechanisms underlying the generation, differentiation, survival and connectivity of nigrostriatal dopaminergic neurons and translate this knowledge into radically new therapeutic strategies for Parkinsons disease (PD). MOLPARK brings together two industrial partners and 6 world-renowned academic groups with a uniquely advantageous knowledge platform based on complementary state-of-the-art technologies and recent relevant discoveries in their laboratories. These include, unique approaches for stem cell renewal control based on novel insights into the function of GABA receptors and intracellular signaling components such as Bex1, novel neurotrophic factors for dopaminergic neurons such as CDNF and MANF, novel approaches to harness the power of GDNF and Wnt proteins for stimulating the growth of dopaminergic terminals and novel ways to enhance synaptogenesis, MOLPARKs strategy is based on four major interrelated objectives. I). Define the mechanisms of stem cell self-renewal, differentiation and integration and exploit these mechanisms to induce or boost existing self-repair processes with the aim of replenishing neurons in PD. 2). Define the mechanisms for sustaining dopaminergic neuron survival in health and disease with the aim of developing new, effective growth factor-based therapies aimed at protecting neurons in PD. 3). Define the mechanisms that promote the growth of DA nigrostriatal axons and dendrites with the aim of identifying therapeutic strategies based on restoring neural processes in PD. 4). Define the mechanisms that promote and sustain the synaptic connections of dopaminergic neurons with the aim of restoring connections in PD.


Wannberg J.,KDev Exploratory AB | Wannberg J.,Uppsala University | Wallinder C.,Uppsala University | Unlusoy M.,Uppsala University | And 2 more authors.
Journal of Organic Chemistry | Year: 2013

A convenient procedure for converting aryl alcohols to aryl fluorides via aryl nonafluorobutylsulfonates (ArONf) is presented. Moderate to good one-pot, two-step yields were achieved by this nonaflation and microwave-assisted, palladium-catalyzed fluorination sequence. The reductive elimination step was investigated by DFT calculations to compare fluorination with chlorination, proving a larger thermodynamic driving force for the aryl fluoride product. Finally, a key aryl fluoride intermediate for the synthesis of a potent HCV NS3 protease inhibitor was smoothly prepared with the novel protocol. © 2013 American Chemical Society.


Leclerc P.,Karolinska Institutet | Pawelzik S.-C.,Karolinska Institutet | Idborg H.,Karolinska Institutet | Idborg H.,KDev Exploratory AB | And 7 more authors.
Prostaglandins and Other Lipid Mediators | Year: 2013

Microsomal prostaglandin E synthase (mPGES)-1 inhibition has been proposed as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. This novel approach could potentially mitigate the gastro-intestinal and cardiovascular side effects seen after long-term treatment with traditional non-steroidal anti-inflammatory drugs (NSAIDs) and Coxibs respectively. Several human mPGES-1 inhibitors have been developed in the recent years. However, they were all shown to be considerably less active on rodent mPGES-1, precluding the study of mPGES-1 inhibition in rodent models of inflammation and pain. The aim of this study was to characterize the new mPGES-1 inhibitor compound II, a pyrazolone that has similar potency on rat and human recombinant mPGES-1, in experimental models of inflammation. In cell culture, compound II inhibited PGE2 production in synovial fibroblasts from patients with rheumatoid arthritis (RASF) and in rat peritoneal macrophages. In vivo, compound II was first characterized in the rat air pouch model of inflammation where treatment inhibited intra-pouch PGE2 production. Compound II was also investigated in a rat adjuvant-induced arthritis model where it attenuated both the acute and delayed inflammatory responses. In conclusion, compound II represents a valuable pharmacological tool for the study of mPGES-1 inhibition in rat models. © 2013 Elsevier Inc. All rights reserved.


Leclerc P.,Karolinska Institutet | Idborg H.,Karolinska Institutet | Idborg H.,KDev Exploratory AB | Idborg H.,NovaSAID AB | And 11 more authors.
Prostaglandins and Other Lipid Mediators | Year: 2013

Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III) and studied its impact on the prostanoid profile in various models of inflammation. Compound III is a benzoimidazole, which has a submicromolar IC50 in both human and rat recombinant mPGES-1. In cellular assays, it reduced PGE2 production in A549 cells, mouse macrophages and blood, causing a shunt to the prostacyclin pathway in the former two systems. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE2 production and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE2 production and tended to decrease the levels of other prostanoids. © 2013 Elsevier Ltd. All rights reserved.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.1.2-5;HEALTH-2007-2.3.1-1 | Award Amount: 7.13M | Year: 2009

Despite the advent of the antibiotic era, infectious diseases retain their pre-eminent position as major worldwide causes of morbidity and mortality. This problem has been worsen by the emergence of multi-antibiotic resistant bacteria and the failure of Pharmaceutical company drug discovery programmes to design antibiotics with truly novel modes of action. NABATIVI has put together a unique consortium made of six academic insitutions and three highly recognized SMEs with complementary expertise in the fields of molecular pathogenicity and broad expertise in drug discovery, optimisation, preclinical development. The consortium has been specifically designed to generate new strategies leading to the identification and validation of novel targets for antimicrobials using as model organisms the gram-negatives Pseudomonas aeruginosa and Burkholderia cenocepacia as they are key agents of morbidity and mortality worldwide in a wide range of diseases. The versatility of these model bacteria will enable the results obtained to be extrapolated to other bacterial pathogens. The extensive involvement of SMEs in this consortium will enable the selection of lead compounds against the identified targets from their large libraries of natural and synthetic chemicals which after validation will establish the basis for the development of new classes of antibacterial drugs. This will result in a reduction in the incidence and improvement of the treatment of infections caused by these organisms with a direct impact on the quality of life and the life expectancy of the affected risk patient populations.

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