Leiden, Netherlands
Leiden, Netherlands

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Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.1-4;HEALTH-2007-2.4.1-8 | Award Amount: 4.20M | Year: 2008

Recently the zebrafish has emerged as a new important system for cancer research because the zebrafish genome contains all orthologs of human oncogenes and forms tumors with similar histopathological and gene profiling features as human tumors. The zebrafish provides an in vivo vertebrate model for identifying novel mechanisms of cancer progression and for development of new anticancer compounds in a time- and cost-effective manner. The ZF-CANCER project aims to develop high-throughput bioassays for target discovery and rapid drug screenings applicable in preclinical validation pipelines. Fluorescently labelled human and zebrafish cancer cells will be implanted (xenogenic and allogenic transplantation) into zebrafish embryos transgenic for a GFP-vascular marker and quantitative, multi-colour fluorescent intravital bio-imaging of tumour progression will be set up as the readout. Because of its amenability to genetic manipulation and optical transparency, the zebrafish is currently the only vertebrate model that allows the simultaneous in vivo imaging of all hallmarks of cancer progression including cell survival, proliferation, migration and induction of angiogenesis. The combination of visual, non- invasive monitoring in translucent host embryos with powerful RNA interference technology, successfully developed for human cancer cells will enable identification of novel targets in a wide variety of human cancers. Automation of these fluorescent readouts will accelerate the screening process with chemical libraries to discover new compounds involved in different aspects of cancer progression and inhibition. In the case study, a selected panel of genes and lead compounds will be screened on a high-throughput platform, possibly resulting in the identification of important anti-tumour drugs relevant for human cancer therapy. Fundamental knowledge, tools and technical expertise gained from ZF-CANCER will be commercially exploited by one company and two high-tech SMEs.


Grant
Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.87M | Year: 2015

The IMPRESS European Training Network will provide a new generation of researchers with the multidisciplinary skills and competences needed to oversee new stocking strategies for Europes most important and threatened freshwater fish species (Atlantic salmon, European eel and sturgeons) thus enabling conservation and growth in a sector of significant economic and societal importance. Freshwater fish populations bring many benefits to Europes citizens through leisure activities, and enhance rural employment through fishing and tourism. The species included in IMPRESS are sentinel species of clean, healthy freshwater ecosystems and of major historical, cultural and economic importance. Over-exploitation and anthropogenic activities have critically endangered wild populations of these fish groups, especially sturgeons. As the main flaw of past stock enhancement is high post-release mortality, the researcher training in IMPRESS will build upon recent scientific advances, especially in fish genomics and enriched hatchery techniques, to develop innovative production regimes resulting in increased survival rates of released fish. This paradigm shift in stock enhancement strategies will require changes at every level of the production cycle, from broodstock management and gamete quality to hatchery design. New in vitro and -omics technologies will be developed to solve current bottlenecks in the production cycle of sturgeons. IMPRESS will also verse young researchers on the social dimensions of this complex issue, including the need to foster closer dialogue with the important stakeholders responsible for national and regional stocking programmes. Further, through dissemination and public engagement, all IMPRESS fellows will work actively to increase public awareness on the importance of these key fish species to freshwater biodiversity, and on the major societal benefits of healthy fish populations, both for recreational activities and for supporting rural employment.


Grant
Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2011-ITN | Award Amount: 3.74M | Year: 2012

Infectious diseases caused by pathogenic micro-organisms are major causes of death, disability, and social and economic disruption for millions of people. During evolution these pathogens have developed intricate strategies to manipulate host defence mechanisms and outwit the immune system. To reduce the burden of infectious diseases it is important to increase understanding of these host-pathogen interaction mechanisms and to develop more effective strategies for drug discovery. The zebrafish holds much promise as a high-throughput drug screening model. In the last few years, zebrafish models for studying human pathogens or closely related animal pathogens have emerged at a rapid pace. The fact that zebrafish produce large amounts of embryos, which develop externally and are optically transparent, gives unprecedented possibilities for live imaging of disease processes and is the basis of novel high-thoughput drug screening approaches. In recent years good models have been developed for toxicity, safety and efficacy of drug screening in zebrafish embryos. However, the major bottleneck for development of high-throughput antimicrobial drug screens has been that infection models rely on manual injection and handling of zebrafish embryos. This limiting factor has been overcome by a unique automated injection system that will be applied in this project. The FishForPharma training network brings together leading European research groups that have pioneered the use of zebrafish infection models and partners from the Biotech and Pharma sectors that aim to commercialise zebrafish tools for biomedical applications. FishForPharma aims to deliver the proof-of-principle for drug discovery using zebrafish infectious disease models and to increase understanding of host-pathogen interaction mechanisms to identify new drug targets for infectious disease treatment. Most importantly, we aim to equip a cohort of young researchers with the knowledge and skills to achieve these goals.


Grant
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: SFS-10a-2014 | Award Amount: 8.10M | Year: 2015

European aquaculture production provides direct employment to 80,000 people and a 3-billion annual turnover. Parasites cause severe disease outbreaks and high economic losses in finfish aquaculture. The overarching goal of ParaFishControl is to increase the sustainability and competitiveness of European Aquaculture by improving understanding of fish-parasite interactions and by developing innovative solutions and tools for the prevention, control and mitigation of the major parasites affecting Atlantic salmon, rainbow trout, common carp, European sea bass, gilthead sea bream and turbot. To achieve these objectives, ParaFishControl brings together a multidisciplinary consortium comprising 30 partners possessing world-leading, complementary, cross-cutting expertise and drawn from public and private research organisations, and the aquaculture industry. The consortium has access to excellent research facilities, diverse biological resources including host-parasite models, and state-of-the-art vaccinology, genomic, proteomic and transcriptomic technologies. The project will: 1) generate new scientific knowledge on key fish parasites, including genomics, life-cycle, invasion strategy and host-parasite interaction data, with special emphasis on host immunity, pathogen virulence and immunomodulation, providing a scientific basis for improved prophylaxis; 2) determine the transfer of parasites between farmed and wild host populations; 3) develop a wide range of novel prophylactic measures, including vaccines and functional feeds; 4) provide a range of advanced or alternative treatments for parasitic diseases; 5) develop cost-effective, specific and sensitive diagnostic tools for key parasitic diseases; 6) assess the risk factors involved in the emergence, transmission and pathogenesis of parasitic diseases; 7) map the zoonotic risks due to fish helminths and; 8) provide a catalogue of good husbandry practices to obtain safe and high-quality fish products.


Jimenez-Amilburu V.,Max Planck Institute for Heart and Lung Research | Jong-Raadsen S.,ZF screens BV | Bakkers J.,University Utrecht | Spaink H.P.,Leiden University | Marin-Juez R.,ZF screens BV
Journal of Endocrinology | Year: 2015

Cardiomyopathies-associated metabolic pathologies (e.g., type 2 diabetes and insulin resistance) are a leading cause of mortality. It is known that the association between these pathologies works in both directions, for which heart failure can lead to metabolic derangements such as insulin resistance. This intricate crosstalk exemplifies the importance of a fine coordination between one of the most energy-demanding organs and an equilibrated carbohydrate metabolism. In this light, to assist in the understanding of the role of insulinregulated glucose transporters (GLUTs) and the development of cardiomyopathies, we have developed a model for glut12 deficiency in zebrafish. GLUT12 is a novel insulin-regulated GLUT expressed in the main insulin-sensitive tissues, such as cardiac muscle, skeletal muscle, and adipose tissue. In this study, we show that glut12 knockdown impacts the development of the embryonic heart resulting in abnormal valve formation. Moreover, glut12-deficient embryos also exhibited poor glycemic control. Glucose measurements showed that these larvae were hyperglycemic and resistant to insulin administration. Transcriptome analysis demonstrated that a number of genes known to be important in cardiac development and function as well as metabolic mediators were dysregulated in these larvae. These results indicate that glut12 is an essential GLUT in the heart where the reduction in glucose uptake due to glut12 deficiency leads to heart failure presumably due to the lack of glucose as energy substrate. In addition, the diabetic phenotype displayed by these larvae after glut12 abrogation highlights the importance of this GLUT during early developmental stages. © 2015 Society for Endocrinology.


Marin-Juez R.,University of Barcelona | Marin-Juez R.,ZF screens B.V. | Rovira M.,University of Barcelona | Crespo D.,University of Barcelona | And 4 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2015

Glucose transporter 2 (GLUT2; gene name SLC2A2) has a key role in the regulation of glucose dynamics in organs central to metabolism. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, its role in the brain is not well understood. To decipher the role of GLUT2 in brain development, we knocked down slc2a2 (glut2), the functional ortholog of human GLUT2, in zebrafish. Abrogation of glut2 led to defective brain organogenesis, reduced glucose uptake and increased programmed cell death in the brain. Coinciding with the observed localization of glut2 expression in the zebrafish hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a but not those expressing neurod. Specificity of the morphant phenotype was demonstrated by the restoration of brain organogenesis, whole-embryo glucose uptake, brain apoptosis, and expression of proneural markers in rescue experiments. These results indicate that glut2 has an essential role during brain development by facilitating the uptake and availability of glucose and support the involvement of glut2 in brain glucose sensing. © 2015 ISCBFM. All rights reserved.


Schartl M.,University of Würzburg | Kneitz S.,University of Würzburg | Wilde B.,University of Würzburg | Wagner T.,University of Würzburg | And 3 more authors.
PLoS ONE | Year: 2012

Aberrations in gene expression are a hallmark of cancer cells. Differential tumor-specific transcript levels of single genes or whole sets of genes may be critical for the neoplastic phenotype and important for therapeutic considerations or useful as biomarkers. As an approach to filter out such relevant expression differences from the plethora of changes noted in global expression profiling studies, we searched for changes of gene expression levels that are conserved. Transcriptomes from massive parallel sequencing of different types of melanoma from medaka were generated and compared to microarray datasets from zebrafish and human melanoma. This revealed molecular conservation at various levels between fish models and human tumors providing a useful strategy for identifying expression signatures strongly associated with disease phenotypes and uncovering new melanoma molecules. © 2012 Schartl et al.


Marin-Juez R.,ZF Screens BV | Jong-Raadsen S.,ZF Screens BV | Yang S.,Leiden University | Spaink H.P.,Leiden University
Journal of Endocrinology | Year: 2014

Type 2 diabetes, obesity, and metabolic syndrome are pathologies where insulin resistance plays a central role, and that affect a large population worldwide. These pathologies are usually associated with a dysregulation of insulin secretion leading to a chronic exposure of the tissues to high insulin levels (i.e. hyperinsulinemia), which diminishes the concentration of key downstream elements, causing insulin resistance. The complexity of the study of insulin resistance arises from the heterogeneity of the metabolic states where it is observed. To contribute to the understanding of the mechanisms triggering insulin resistance, we have developed a zebrafish model to study insulin metabolism and its associated disorders. Zebrafish larvae appeared to be sensitive to human recombinant insulin, becoming insulin-resistant when exposed to a high dose of the hormone. Moreover RNA-seq-based transcriptomic profiling of these larvae revealed a strong downregulation of a number of immune-relevant genes as a consequence of the exposure to hyperinsulinemia. Interestingly, as an exception, the negative immune modulator protein tyrosine phosphatase nonreceptor type 6 (ptpn6) appeared to be upregulated in insulin-resistant larvae. Knockdown of ptpn6 was found to counteract the observed downregulation of the immune system and insulin signaling pathway caused by hyperinsulinemia. These results indicate that ptpn6 is a mediator of the metabolic switch between insulin-sensitive and insulin-resistant states. Our zebrafish model for hyperinsulinemia has therefore demonstrated its suitability for discovery of novel regulators of insulin resistance. In addition, our data will be very useful in further studies of the function of immunological determinants in a non-obese model system. © 2014 Society for Endocrinology.


Boetzer M.,BaseClear B.V. | Boetzer M.,Leiden University | Henkel C.V.,ZF screens B.V. | Jansen H.J.,ZF screens B.V. | And 2 more authors.
Bioinformatics | Year: 2011

Summary: De novo assembly tools play a main role in reconstructing genomes from next-generation sequencing (NGS) data and usually yield a number of contigs. Using paired-read sequencing data it is possible to assess the order, distance and orientation of contigs and combine them into so-called scaffolds. Although the latter process is a crucial step in finishing genomes, scaffolding algorithms are often built-in functions in de novo assembly tools and cannot be independently controlled. We here present a new tool, called SSPACE, which is a stand-alone scaffolder of pre-assembled contigs using paired-read data. Main features are: a short runtime, multiple library input of paired-end and/or mate pair datasets and possible contig extension with unmapped sequence reads. SSPACE shows promising results on both prokaryote and eukaryote genomic testsets where the amount of initial contigs was reduced by at least 75%. © The Author 2010. Published by Oxford University Press.


Patent
Zf Screens B.V. | Date: 2010-07-08

Provided is a method and system for screening chemical compounds or compositions, wherein replicating entities are introduced into the yolk of an (un)fertilized egg or embryo. The method may be extended to elucidate the mechanism-of-action of functional chemical compounds or compositions in the same method and system. The method and system may also be employed for identifying marker genes, marker proteins or marker metabolites.

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