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Cambridge, United Kingdom

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Grant
Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-ITN-2008 | Award Amount: 4.61M | Year: 2009

Chromatin packages a few meters of DNA into a nucleus measuring a few microns. This tight folding occurs by assembling DNA with histones into so-called nucleosomes, thus ensuring the mechanical stability of our genome. On the flipside, this makes nucleosomes a formidable obstacle to the machines that read, copy or repair its DNA message. One of the fundamental questions in biology is to understand how nucleosome structure is established, maintained and manipulated. Our Marie Curie Initial Training Network will carry out multidisciplinary, collaborative research projects focused on deciphering nucleosome structure and function in space and time (Nucleosome4D). Our main objective is to provide our young researchers with world-class research & training in nucleosome biology. We will use cutting-edge, interdisciplinary methods and collaborative projects to determine how nucleosomes are remodeled during transcription, when genes are silenced, as cell divide, as stem cells differentiate, during organismal development and in human disease. We utilize state-of-the-art approaches in structural biology, biophysics, cell biology, live-cell imaging, biochemistry, genetics, genomics and bioinformatics. We will implement a comprehensive training plan for scientific and career development using the best local approaches to research & training, by promoting exchanges, using the advise of our industrial partners and three Visiting Scientists, by sharing reagents and expertise, as well as through a structured set of scientific workshops and complementary skills training courses. Together, our effort will ensure the multidisciplinary and intersectorial training of a new cohort of young European researchers. This will allow our trainees to take the opportunities and meet the challenges of a successful career in the life science sector through excellent training, effective communication, great teamwork and proven project management skills.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.1.2-1 | Award Amount: 14.94M | Year: 2010

AIM: To identify the molecular mechanisms characterizing cilium function, and the discrete perturbations associated with dysfunction caused by mutations in inherited ciliopathies, applying a systems biology approach. BACKGROUND: Cilia are microtubule-based, centriole-derived projections from the cell surface. They transduce extracellular signals and regulate key processes in which signals of the extracellular environment are translated into a cellular response, such as cell cycle control, Wnt signalling, Shh signalling and planar cell polarity. Disruption of cilium-based processes by mutations can cause very severe disorders. Many of these ciliopathies have overlapping phenotypes. There is evidence, that ciliary proteins are organized in cell/context specific complexes and/or in shared regulatory circuits in cilia of affected tissues. Yet, knowledge of the composition, wiring, dynamics and associated signaling pathways of the corresponding molecular building blocks and associated protein networks remains very limited. APPROACH: We propose here that ciliopathies can be considered systemically as specific perturbations in a versatile dynamically regulated multifunctional molecular machine. Mainly based on the comprehensive description of the ciliary interactome, quantitative functional assays as well as human genetic data derived from ciliopathy patients, we will generate a comprehensive stream of content-rich quantitative data towards systemic analysis of ciliar function. These data will be used to generate and validate discrete models that describe functional modules and regulatory circuits in the ciliome as well as predicting biological context specific features of cilia as well as perturbations leading to ciliopathies. This will enable us to 1) understand the systemic features of discrete ciliary functions, 2) scrutinize the molecular disease mechanisms of different overlapping ciliopathies, and 3) develop therapeutic strategies towards improved treatment.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.4.2-9-5 | Award Amount: 9.70M | Year: 2011

NOTOX will develop and establish a spectrum of systems biological tools including experimental and computational methods for i) organotypic human cell cultures suitable for long term toxicity testing and ii) the identification and analysis of pathways of toxicological relevance. NOTOX will initially use available human HepaRG and primary liver cells as well as mouse small intestine cultures in 3D systems to generate own experimental data to develop and validate predictive mathematical and bioinformatic models characterizing long term toxicity responses. Cellular activities will be monitored continuously by comprehensive analysis of released metabolites, peptides and proteins and by estimation of metabolic fluxes using 13C labelling techniques (fluxomics). At selected time points a part of the cells will be removed for in-depth structural (3D-optical and electron microscopy tomography), transcriptomic, epigenomic, metabolomic, proteomic and fluxomic characterizations. When applicable, cells derived from human stem cells (hESC or iPS) and available human organ simulating systems or even a multi-organ platform developed in SCREENTOX and HEMIBIO will be investigated using developed methods. Together with curated literature and genomic data these toxicological data will be organised in a toxicological database (cooperation with DETECTIVE, COSMOS and TOXBANK). Physiological data including metabolism of test compounds will be incorporated into large-scale computer models that are based on material balancing and kinetics. Various -omics data and 3D structural information from organotypic cultures will be integrated using correlative bioinformatic tools. These data also serve as a basis for large scale mathematical models. The overall objectives are to identify cellular and molecular signatures allowing prediction of long term toxicity, to design experimental systems for the identification of predictive endpoints and to integrate these into causal computer models.


Boldt K.,University of Tübingen | Van Reeuwijk J.,Radboud University Nijmegen | Lu Q.,University of Heidelberg | Koutroumpas K.,Genopole | And 95 more authors.
Nature Communications | Year: 2016

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine. © 2016, Nature Publishing Group. All rights reserved.


Betts M.J.,University of Heidelberg | Lu Q.,University of Heidelberg | Jiang Y.,University of Heidelberg | Drusko A.,University of Heidelberg | And 16 more authors.
Nucleic Acids Research | Year: 2015

Systematic interrogation of mutation or protein modification data is important to identify sites with functional consequences and to deduce global consequences from large data sets. Mechismo (mechismo.russellab.org) enables simultaneous consideration of thousands of 3D structures and biomolecular interactions to predict rapidly mechanistic consequences for mutations and modifications. As useful functional information often only comes from homologous proteins, we benchmarked the accuracy of predictions as a function of protein/structure sequence similarity, which permits the use of relatively weak sequence similarities with an appropriate confidence measure. For protein-protein, protein-nucleic acid and a subset of protein-chemical interactions, we also developed and benchmarked a measure of whether modifications are likely to enhance or diminish the interactions, which can assist the detection of modifications with specific effects. Analysis of high-throughput sequencing data shows that the approach can identify interesting differences between cancers, and application to proteomics data finds potential mechanistic insights for how post-translational modifications can alter biomolecular interactions. © 2015 The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.


Kalinina O.V.,University of Heidelberg | Kalinina O.V.,Max Planck Institute for Informatics | Wichmann O.,University of Heidelberg | Apic G.,University of Heidelberg | And 2 more authors.
Nucleic Acids Research | Year: 2012

Progress in structure determination methods means that the set of experimentally determined 3D structures of proteins in complex with small molecules is growing exponentially. ProtChemSI exploits and extends this useful set of structures by both collecting and annotating the existing data as well as providing models of potential complexes inferred by protein or chemical structure similarity. The database currently includes 7704 proteins from 1803 organisms, 11 324 chemical compounds and 202 289 complexes including 178 974 predicted. It is publicly available at http://pcidb.russelllab.org. © The Author(s) 2011. Published by Oxford University Press.


Apic G.,University of Heidelberg | Apic G.,Cambridge Cell Networks Ltd. | Betts M.J.,University of Heidelberg | Russell R.B.,University of Heidelberg
PLoS ONE | Year: 2011

Indicators that rank countries according socioeconomic measurements are important tools for regional development and political reform. Those currently in widespread use are sometimes criticized for a lack of reproducibility or the inability to compare values over time, necessitating simple, fast and systematic measures. Here, we applied the 'guilt by association' principle often used in biological networks to the information network within the online encyclopedia Wikipedia to create an indicator quantifying the degree to which pages linked to a country are disputed by contributors. The indicator correlates with metrics of governance, political or economic stability about as well as they correlate with each other, and though faster and simpler, it is remarkably stable over time despite constant changes in the underlying disputes. For some countries, changes over a four year period appear to correlate with world events related to conflicts or economic problems. © 2011 Apic et al.


Kalinina O.V.,University of Heidelberg | Kalinina O.V.,Russian Academy of Sciences | Wichmann O.,University of Heidelberg | Apic G.,University of Heidelberg | And 2 more authors.
PLoS Computational Biology | Year: 2011

Biological networks are powerful tools for predicting undocumented relationships between molecules. The underlying principle is that existing interactions between molecules can be used to predict new interactions. Here we use this principle to suggest new protein-chemical interactions via the network derived from three-dimensional structures. For pairs of proteins sharing a common ligand, we use protein and chemical superimpositions combined with fast structural compatibility screens to predict whether additional compounds bound by one protein would bind the other. The method reproduces 84% of complexes in a benchmark, and we make many predictions that would not be possible using conventional modeling techniques. Within 19,578 novel predicted interactions are 7,793 involving 718 drugs, including filaminast, coumarin, alitretonin and erlotinib. The growth rate of confident predictions is twice that of experimental complexes, meaning that a complete structural drug-protein repertoire will be available at least ten years earlier than by X-ray and NMR techniques alone. © 2011 Kalinina et al.


PubMed | University of Tübingen, University Utrecht, University College London, University College Dublin and 11 more.
Type: | Journal: Nature communications | Year: 2016

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.

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