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Grant
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: SC1-PM-04-2016 | Award Amount: 9.99M | Year: 2017

Sudden cardiac arrest (SCA) causes ~20% of all deaths in Europe. SCA is lethal within minutes if left untreated and survival rates are presently only 5-20%. Therefore, there is a large medical need to improve SCA prevention and treatment. Designing effective individualized prevention and treatment strategies requires knowledge on genetic and environmental risk factors. So far, these efforts have been hampered by the lack of sufficiently large study cohorts of SCA patients with detailed information. Obtaining SCA patient samples is challenging as the condition happens suddenly and unexpectedly. In this project, leading European scientific teams which have created large relevant population cohorts, mostly dedicated to SCA research, join forces to fully exploit available data towards improving SCA management. This will be done by: - Building an unique and growing database of >100.000 (DNA) samples including >20.000 SCA patient samples, by combining existing European databases and infrastructures. - Identifying risk factors (inherited, acquired, environmental) and first-response treatment strategies that may explain the differences in SCA occurrence and survival between European countries - Collaborating with professional networks, such as the European Heart Rhythm Association, and European Resuscitation Council, to translate the outcomes into changes in clinical practice and influencing European health policies on SCA management.


Grant
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: Health | Award Amount: 2.85M | Year: 2014

The ongoing Ebola outbreak in West Africa is the largest and deadliest the world has ever seen. In September 2014, the number of EBOV cases exceeded the total of all cases from previous known outbreaks. Further, this public health crisis shifted into a complex emergency, with significant, social, economic, humanitarian, political and security dimensions. Till date, no effective medicine has been proven to be effective against EBOV. As a result, it is immensely difficult to mitigate the current outbreak as well as prevent further outbreaks in this region. On Sept 4-5 2014, the WHO gathered expertise on experimental therapies and vaccines and their role in containing the Ebola outbreak in West Africa. During this consultation, experts identified several therapeutic and vaccine interventions that should be the focus of priority evaluation. Among these candidates is the existing antiviral drug Favipiravir, that has proven activity against many RNA viruses in vivo and in vitro including Ebola. Favipiravir is known to inhibit viral gene replication within infected cells to prevent propagation among which it inhibits viral gene replication within infected cells to prevent propagation. Hence, Favipiravir is currently aimed as a curative option in severe pandemic flue. Furthermore, there is currently enough stock of Favipiravir to even treat more than 20.000 patients, and the producer of Favipiravir, Toyoma Chemical/Fujifilm in Japan is willing to rapidly upscale the production of this drug. This drug has been extensively tested in humans and approved in Japan for treatment and prevention of influenza. The drug has shown an excellent safety profile in more than 2000 patients tested and no major adverse effect were reported. The current crisis requires both an immediate response to treat patients and prevent the further spread of the epidemic, as well as long term commitment in the complex sociocultural context. REACTION! will address both needs.


Motifs D.,University Utrecht | da Silva Almeida A.C.,Drug Discovery Factory BV | Strous G.J.,University Utrecht | van Rossum A.G.S.H.,Drug Discovery Factory BV
Molecular Endocrinology | Year: 2012

The physiological roles of GH are broad and include metabolism regulation and promotion of somatic growth. Therefore, the responsiveness of cells to GH must be tightly regulated. This is mainly achieved by a complex and well-controlled mechanism of GH receptor (GHR) endocytosis. GHR endocytosis occurs independently of GH and requires the ubiquitin ligase, SCF (βTrCP) that is recruited to the ubiquitin-dependent endocytosis (UbE) motif in the cytoplasmic tail of the GHR. In this study we report that, in addition to the UbE motif, a downstream degron, DSGRTS, binds to βTrCP. The WD40 residues on βTrCP involved in the interaction with this sequence are identical to the ones necessary for binding the classical motif, DSGxxS, in inhibitor of NF_B signalling, and _-catenin. Previously, we showed that this motif is not involved in GH-induced endocytosis. We show here that the DSGRTS sequence significantly contributes to GHR endocytosis/degradation in basal conditions, whereas the UbE motif is involved both in basal and GH-induced conditions. These findings explain the high rate of GHR degradation under basal conditions, which is important for regulating the responsiveness of cells to GH. © 2012 by The Endocrine Society.


Da Silva Almeida A.C.,University Utrecht | Da Silva Almeida A.C.,Drug Discovery Factory BV | Hocking H.G.,University Utrecht | Boelens R.,University Utrecht | And 3 more authors.
Biochemical Journal | Year: 2013

GH (growth hormone) binding to the GHR (GH receptor) triggers essential signalling pathways that promote growth and metabolic regulation. The sensitivity of the cells to GH is mainly controlled by the endocytosis of the receptor via βTrCP (β-transducin repeat-containing protein). In the present study, we show that βTrCP interacts directly via its WD40 domain with the UbE (ubiquitin-dependent endocytosis) motif in GHR, promoting GHR ubiquitination in vitro. NMR experiments demonstrated that the UbE motif is essentially unstructured, and, together with functional mapping of the UbE and βTrCP WD40 residues necessary for binding, led to a unique interaction model of βTrCP with GHR-UbE. This interaction is different from the conventional βTrCP-substrate interactions described to date. This interaction therefore represents a promising specific target to develop drugs that inhibit GHR endocytosis and increase GH sensitivity in cachexia patients. © The Authors Journal compilation © 2013 Biochemical Society.


Putters J.,University Utrecht | da Silva Almeida A.C.,University Utrecht | da Silva Almeida A.C.,Drug Discovery Factory BV | van Kerkhof P.,University Utrecht | And 4 more authors.
PLoS ONE | Year: 2011

Background: Length and intensity of signal transduction via cytokine receptors is precisely regulated. Degradation of certain cytokine receptors is mediated by the ubiquitin ligase SCF(βTrCP). In several instances, Janus kinase (Jak) family members can stabilise their cognate cytokine receptors at the cell surface. Principal Findings: In this study we show in Hek293 cells that Jak2 binding to the growth hormone receptor prevents endocytosis in a non-catalytic manner. Following receptor activation, the detachment of phosphorylated Jak2 induces down-regulation of the growth hormone receptor by SCF(βTrCP). Using γ2A human fibroblast cells we show that both growth hormone-induced and constitutive growth hormone receptor endocytosis depend on the same factors, strongly suggesting that the modes of endocytosis are identical. Different Jak2 RNA levels in HepG2, IM9 and Hek293 cells indicate the importance of cellular concentration on growth hormone receptor function. Both Jak2 and βTrCP bind to neighbouring linear motifs in the growth hormone receptor tail without the requirement of modifications, indicating that growth hormone sensitivity is regulated by the cellular level of non-committed Jak2. Conclusions/Significance: As signal transduction of many cytokine receptors depends on Jak2, the study suggests an integrative role of Jak2 in cytokine responses based on its enzyme activity as well as its stabilising properties towards the receptors. © 2011 Putters et al.


Putters J.,University Utrecht | Putters J.,Drug Discovery Factory BV | Slotman J.A.,University Utrecht | Gerlach J.P.,University Utrecht | Strous G.J.,University Utrecht
Cellular Signalling | Year: 2011

SCFβTrCP is the ubiquitin ligase for a wide variety of substrates and functions in many cellular processes. βTrCP, the substrate binding factor of the SCF complex, has two isoforms, produced from different genes, and several splice variants. Despite a certain level of redundancy, knock-out studies show different phenotypes indicating different preferential substrates for the two isoforms. However, until now functional differences between βTrCP1 and 2 were not studied at the endogenous protein level. We generated isoform-specific antibodies against βTrCP to characterise endogenous βTrCP isoforms and splice variants. We show that endogenous βTrCP1 and 2 localise to both nucleus and cytosol. Interestingly, we find that one splice variant of βTrCP2 localises exclusively to the nucleus and another only to the cytosol. In addition, we show that the substrate binding domain of βTrCP is the dominant localisation determinant. © 2010 Elsevier Inc.

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