A systems approach to understanding lipid, Ca2+ and MAPK signalling networks

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Sensing and interpreting external stimulus often involves the recruitment of several cross-regulating signalling pathways. NLN has been studying for many years the biochemical determinant of neuroadaptation. In the chosen model system, the medium-sized spiny neuron of the striatum (existing and planned uplft grant funded work in the lab of MC are focused on this class of neurons giving us significant mass and focus within the ISP), synaptic plasticity and dendritic remodeling, involve several intracellular kinase-dependent signalling pathways acting with different timescales(131). For instance, CaMKII, PI3K and PKC trigger short-term plasticity in seconds through protein modifications and translocation. PKA, ERK (MAPK) and CaMKIV persistently modulate gene regulatory networks and change gene expression. TrkB, a tyrosine kinase receptor for neurotrophins and PI3K/PKB are also involved in long-term effects on for instance dendritic remodelling and neuronal survival. All these kinase pathways are linked through the activation/inhibition of phosphatases, ultimately forming a network of kinases, phosphatases and substrate phosphoproteins with variable dynamics. However, at present the knowledge of these phosphorylation-dependent signalling pathways remains fragmented and largely descriptive. NLN's activity at the BI will follow two lines. (i) He will continue to study the role of Ca2+ signals in synaptic plasticity, developing highly realistic models and benefiting from Llew Roderick’s (Epigenetcis ISPG) expertise in Ca2+ analysis. Those models will help in understanding the respective roles of the proteins constituting the Ca2+-sensitive, long-term potentiation cycle - glutamate ionotropic receptors, calmodulin, neurogranin, calcineurin and CaMKII – in decoding amplitude, frequency and duration of Ca2+ signals. A better grasp Ca2+ homeostasis and dynamics is now acknowledged to be a key to understanding synaptic ageing(132, 133). (ii) NLN's group will use synaptic signalling as a model system to understand the mechanisms and consequences of integrating multiple signalling pathways.

Publications

10 25 50

 
Description 1) We have shown that different perturbations of phosphoinositide signalling triggered large modifications of the transcriptome in human cells. The responses to phosphoinositides sensitive to epidermal growth factor stimulations are more involved in "dynamic" processes (cell migration, wound healing) while the responses insensitive to epidermal growth factor are more involved in "static" processes (cell adhesion, extracellular matrix). We identified Blimp1 as a key transcription factor mediating the former effects. A large proportion of the genes modified by phosphoinotitide signalling perturbations via Blimp1 code for proteins involved in phosphoinotitide signalling itself, revealing a transcriptional feedback loop.

2) We developed a new model of calmodulin, with hemiconcerted conformational switching, which allowed us to understand the observed effects of the synaptic protein Neurogranin on Calmodulin responses to calcium (Lai et al PloS Comput Biol, 2015). Integrating Neurogranin, our existing models of Calcium/Calmodulin Kinase II and a new model of Calcineurin, we showed why Neurogranin controls the basal sensitivity of the synapse to calcium perturbations rather than the dynamic range of the responses, as proposed before.

3) We studied the effect of calcium signalling on diffusion and internalisation of glutamate NMDA receptors, and therefore on synaptic plasticity. In order to investigate the impact of amyloid beta on synaptic function, we incorporated Pyk2/Fyn and Calcineurin/STEP pathways to the model of calicum signalling. The simulations explain the biphasic effect observed after amyloid beta treatment in animal models, with a transient increase of synaptic receptors followed by a long term decrease. These models of synaptic signalling are integrated with models of amyloid beta aggregation in order to provide a multi-scale view of Alzheimer's Disease impact over the lifetime of a population of patients.

3) Using a model incorporating signalling cascades - including MAPK - and gene regulatory networks, we reproduced the observed epigenetics barrier between embryonic and trophoblast stems cells. The initial models, validated against experimental measurement, predicted new perturbations to overcome the barrier such as block of the Stat3 signalling. These predictions are now being tested.

4) To support our modelling activity, we further developed key software tools, such as the JSBML software library, the Systems Biology Format Converter, and standards to encode model and simulation descriptions. These tools benefit the community of systems biology at large, and are well recognised and used in the field.
Exploitation Route A quantitative description of the dynamics of signalling pathways is key to understand their function, predict the effect of perturbations and develop drugs. Our models are provided in standard formats through public repository so that others can re-use and build on them.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Advisor to Science Europe on multi-disciplinarity career paths
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Babraham Institute Representative on Translational Research at EU Life, a consortium of EU Life Sciences Institutes
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
URL http://eu-life.eu/
 
Description Member of Scientific Advisory Board of Cancer Research Technology Discovery Lab
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Membership of Scientific Advisory Board for Cancer Research Technology
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Scientific Advisory Board for CRUK Programme Grant awarded to Northern Institute for Cancer Research, Univeristy of Newcastle
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Scientific advisor to the Research Data Alliance
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Innovate UK
Amount £770,434 (GBP)
Funding ID Innovate UK 
Organisation PhoreMost 
Sector Private
Country Unknown
Start 05/2017 
End 03/2019
 
Title CDKN1C/p57KIP2 KO cell lines 
Description We have used CRISPR/Cas9 gene editing to generate COLO205 cell line clones lacking the CDK inhibitor p57KIP2 encoded by CDKN1C 
Type Of Material Cell line 
Provided To Others? No  
Impact We have used these celsl to demonstrate the role of p57KIP2 in ERK-driven cell cycle arrest. This will form part of a future manuscript. Additional impacts will emerge as we undertake further analysis These will be made available to the community in the future 
 
Title FGFRi resistant cell lines 
Description We have generated gastric, breast and myeloma cells with acquired resistance to AZD4547, an FGFR inhibitor undergoing clinical evaluation, and a second closely related molecule. We have now performed genome-wide gene expression, exome sequencing and phospho-proteomics analysis on parental and resistant cells. 
Type Of Material Cell line 
Year Produced 2013 
Provided To Others? Yes  
Impact We have generated a host of new information on genetic, transcriptomic and biochemical changes associated with acquired resistance to these drugs. We are currently mining this information and testing specific gene products as candidate drivers of resistance. This information is being shared with project partners. This data will be made freely available as each study is published allowing other researchers to access and benefit from our datasets 
 
Title IKKalpha and IKKbeta KO cell lines 
Description We have generated HCT116 cell lines lacking one or other or both (DKO) of the critical NFkB activating protein kinases IKKalpha or IKKbeta using CRISPR/Cas9 gene targeting. 
Type Of Material Cell line 
Provided To Others? No  
Impact Too early for impacts; cells still being charatcerised. These will be made available to the community in the future 
 
Title MEKi resistant tumour cell lines 
Description We have generated a panel of colorectal cancer cell lines (BRAFmut or KRASmut) with acquired resistance to the MEK inhibitor Selumetinib. 
Type Of Material Cell line 
Year Produced 2013 
Provided To Others? Yes  
Impact We have generated a host of new information on genetic, transcriptomic and biochemical changes associated with acquired resistance to these drugs. We are currently mining this information and testing specific gene products as candidate drivers of resistance. This information is being shared with project partners 
 
Title ZFP36 KO cell llines 
Description We have generated HCT116 cell liens in which we have deleted the RNA binding proteins ZFP36L1 or ZFP36L2 - singly or in combination (DKO) using CRISPR/Cas9 gene editing. 
Type Of Material Cell line 
Provided To Others? No  
Impact ZFP36L1 KO cells featured in our 2016 manuscript - Galloway et al Science Further impacts will arise as we undertake further characterisation of these cell lines These will be made available to the community in the future 
 
Title mTORi resistant cell lines 
Description We have generated human cell lines (cancer cells and primary human fibroblasts) with adaptive resistance to the mTOR inhibitors rapamycin and AZD8055 
Type Of Material Cell line 
Year Produced 2012 
Provided To Others? Yes  
Impact Two papers have been published and this has provided insight in to likely mechanisms by which cancer cells may adapt and acquire resistance to mTOR inhibitors 
 
Title BioModels 
Description BioModels Database is a free and open-source repository for storing, exchanging and retrieving quantitative models of biological interest. All the models in the curated section of BioModels Database have been described in peer-reviewed scientific literature. The models stored in the curated branch of BioModels Database are compliant with MIRIAM, the standard of model curation and annotation. The models have been simulated by curators to check that when run in simulations, they provide the same results as described in the publication. Model components are annotated, so the users can conveniently identify each model element and retrieve further information from other resources. 
Type Of Material Database/Collection of data 
Provided To Others? Yes  
Impact BioModels Database has become a worldwide reference resource for systems biology. It is being used by the community in a variety of ways; People search for existing models, to learn about systems' behaviours, or to developer new models. The resource is also used to benchmark different simulation systems, and to study the clustering of models based upon their annotations. Model deposition to the database today is advised by several publishers of scientific journals. Case4Support-Signalling-JeS.pdf 
URL http://www.ebi.ac.uk/biomodels
 
Title DYRK1B transcriptome gene data set 
Description RNA-seq data set derived from HEK293 cells which exhibit Tet-regulated DYRK1B expression Reports genome wide changes in abundance and splicing patterns in response to DYRK1B expression 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Too soon for impacts. Data currently being analsyed 
 
Title DYRK2 Transcriptome gene data set 
Description RNA-seq data set derived from HEK293 cells which exhibit Tet-regulated DYRK2 expression Reports genome wide changes in abundance and splicing patterns in response to DYRK2 expression 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Too soon for impacts. Data currently being analysed 
 
Title DYRK2 phosphoproteomics dataset 
Description Using HEK293 cells exhibiting inducible expression of the DYRK2 protein kinase (HD2 cells) we have performed Phospho-SILAC mess spectrometry to identify DYRK2-inducible phosphoproteins. Some of these turn out to be direct DYRK2 substrates 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact This dataset has allowed us to identify DYRK2-inducible phosphoproteins, including new substrates, providing new insghts into the function of the DYRK2 protein in gene expression, autophagy/proteostasis and cell motility 
 
Title Dutta-Roy AMPA 
Description Concerted model of ligand-dependent openings of the multiple AMPA receptor conductance states. 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? Yes  
Impact Better understanding of synaptic plasticity. 
URL https://identifiers.org/biomodels.db/BIOMD0000000569
 
Title ERK pathway cell cycle arrest/senescence gene data set 
Description Human Illumina bead array describing changes in transcriptome associated with ERK-driven cell cycle arrest/senescence 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact New insights into ERK signalling associated with cell cycle arrest and senescence Identification of new links between ERK signalling the cell cycle Identification of ERK target genes 
 
Title IKKa, IKKb and IKK DKO gene sets 
Description RNAseq data sets from human colorectal epithelial cell lines in which IKKa, IKKb or both IKKs have been deleted by CRISPR/Cas9. Both basal and TNFalpha-induced conditions were employed so that we can define the contribution of IKKs to basal and cytokine-induced gene expression. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact The IKKs are the kinases that drive activation of the NFkappaB (NFkB) transcription factor. This is the first instance of knockout of the IKKs in human cells. We have confirmed the expression of known NFkB target genes but also identified an array of novel IKK-dependent genes that are candidate NFkB gene targets. Some of these have roles in autophagy, protein turnover, protein trafficking, cell motility and inflammation. This data will be made available freely when the first manuscript is published. 
 
Title Illumina mRNA dataset FGFRi 
Description Human Illumina bead array data for comparison of differences in gene expression between parental and FGFRi-resistant KMS11 cells. Referecne paper Chell et al (2013) Oncogene. Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Data contributed to a primary research paper and helped to define the first reported mechanism of acquired resistance to FGFR inhibitors 
URL http://www.ebi.ac.uk/arrayexpress/experiments/E-TABM-1222/
 
Title Kiselev et al PIP3 project 
Description An R package containing all datasets, and scripts/functions needed to reproduce them, from the work described in the publication Kiselev V.Y., Juvin V., Mouhannad M., Luscombe N.M., Hawkins P., Le Novère N., Stephens L.R. Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop. Nucleic Acids Research (2015) 43 (20): 9663-9679 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact n/a 
URL https://github.com/wikiselev/rnaseq.mcf10a
 
Title Lai et al Calmodulin 
Description Hemiconcerted MWC model of intact calmodulin with two targets 
Type Of Material Computer model/algorithm 
Year Produced 2015 
Provided To Others? Yes  
Impact Better understanding of calmodulin regulation by calcium in neurons. 
URL https://identifiers.org/biomodels.db/BIOMD0000000574
 
Title MEKi resistance gene set 
Description Human Illumina bead array descricing genome-wide changes in mRNA expression in parental and MEKi resistant cells 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact One primary research paper and review articles. Demonstration of mechanism by which tumour cells acquire resistance to MEK inhibitors 
 
Title Malek 2017 
Description Computational model of phosphatase activities acting on PIP2 and PIP3 in signalling. 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? Yes  
Impact New understanding of the role of tumor suppressor PTEN on PI(3,4)P2 
URL https://identifiers.org/biomodels.db/MODEL1704190000
 
Title Musante et al 2017 level 1 
Description Computational model of the reciprocal regulations of ARPP-16 by PKA and MAST3 kinases. Mutual inhibitions only. 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? Yes  
Impact Better understanding of PKA signalling in neurons. 
URL https://identifiers.org/biomodels.db/BIOMD0000000643
 
Title Musante et al 2017 level 2 
Description Computational model of the reciprocal regulations of ARPP-16 by PKA and MAST3 kinases. mutual inhibitions and PKA inhibits MAST3 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? Yes  
Impact Better understanding of PKA signalling in neurons. 
URL https://identifiers.org/biomodels.db/BIOMD0000000644
 
Title Musante et al 2017 level 3 
Description Computational model of the reciprocal regulations of ARPP-16 by PKA and MAST3 kinases. mutual inhibitions and PKA inhibits MAST3 and dominant negative effect 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? Yes  
Impact Better understanding of PKA signalling in neurons. 
 
Title RNA-Seq from Kiselev et al 
Description All the RNA-Seq data from the publication Kiselev V.Y., Juvin V., Mouhannad M., Luscombe N.M., Hawkins P., Le Novère N., Stephens L.R. Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop. Nucleic Acids Research (2015) 43 (20): 9663-9679 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact n/a 
URL http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69822
 
Description Angus Nairn 
Organisation Yale University
Country United States 
Sector Academic/University 
PI Contribution Computational analysis of data and mathematical modeling
Collaborator Contribution Experimental data
Impact We discovered the molecular mechanisms by which Protein Kinase A regulates the inhibitory activity of ARPP-16 on Protein Phosphatase 2A. This is a multi-disciplinary collaboration involving experimental and computational biology.
Start Year 2015
 
Description AstraZeneca ERK 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We want to understand the various mechanisms by which ERK1/2 pathway-addicted tumour cells adapt and acquire resistance to the MEK1/2 inhibtor Selumetinib. We have generated a variety of human tumour cell lines with acquired resistance to the clinical candidate MEK1/2 inhibitor Selumetinib. These include cell lines in which BRAF is the driving oncogene but also those in which KRAS is the driving oncogene. We have analysed the activation state of the ERK1/2 pathway in these cells and in some cases validated the resistance mechanism. In other cases this analysis is ongoing. In some models we find that resistance is reversible upon drug withdrawal suggesting that resistant cells actually have a fitness deficit in the absence of drug. We are investigating the mechanisms that underlie this fitness deficit. For our partner (AstraZeneca/CRUK) this may allow development of rational strategies to overcome or delay resistance and thereby provide more durable drug responses. For our own basic biological interests this should provide insights into how this key cell fate signalling pathway is regulated; this may be relevant to emerging regenerative medicine protocols.
Collaborator Contribution AstraZeneca have performed a variety of Next Gen Seq analyses on samples provided by us to identify genetic and transcriptomic changes associated with resistance; these may be candidate resistance drivers. They are also performing xenograft studies to test specific hypotheses that emerge form our studies. Our collaborators at the University of Bath are investigating how the magnitude of ERK1/2 signalling can impart different tumour cell responses when Selumetinib is withdrawn from resistant cells. In a three-way collaboration between our lab, the CRUK-CI and AstraZeneca we are peforming high throughput drug combination screens to identify drugs that combine with Selumetinib to provide superior tumour growth inhibition or tumour cell death.
Impact Much of this is still early stage. However, high throughput drug screening has identified several drug combinations that markedly transform the growth inhibitory effects of Selumetinib. Our analysis of new resistance models has identified several completely novel potential mechanisms which we are in the process of validating. These studies will lead to further papers in addition those publications already reported and may contribute to the testing of new drug combinations in the clinic in the future.
Start Year 2013
 
Description AstraZeneca ERK 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We want to understand the various mechanisms by which ERK1/2 pathway-addicted tumour cells adapt and acquire resistance to the MEK1/2 inhibtor Selumetinib. We have generated a variety of human tumour cell lines with acquired resistance to the clinical candidate MEK1/2 inhibitor Selumetinib. These include cell lines in which BRAF is the driving oncogene but also those in which KRAS is the driving oncogene. We have analysed the activation state of the ERK1/2 pathway in these cells and in some cases validated the resistance mechanism. In other cases this analysis is ongoing. In some models we find that resistance is reversible upon drug withdrawal suggesting that resistant cells actually have a fitness deficit in the absence of drug. We are investigating the mechanisms that underlie this fitness deficit. For our partner (AstraZeneca/CRUK) this may allow development of rational strategies to overcome or delay resistance and thereby provide more durable drug responses. For our own basic biological interests this should provide insights into how this key cell fate signalling pathway is regulated; this may be relevant to emerging regenerative medicine protocols.
Collaborator Contribution AstraZeneca have performed a variety of Next Gen Seq analyses on samples provided by us to identify genetic and transcriptomic changes associated with resistance; these may be candidate resistance drivers. They are also performing xenograft studies to test specific hypotheses that emerge form our studies. Our collaborators at the University of Bath are investigating how the magnitude of ERK1/2 signalling can impart different tumour cell responses when Selumetinib is withdrawn from resistant cells. In a three-way collaboration between our lab, the CRUK-CI and AstraZeneca we are peforming high throughput drug combination screens to identify drugs that combine with Selumetinib to provide superior tumour growth inhibition or tumour cell death.
Impact Much of this is still early stage. However, high throughput drug screening has identified several drug combinations that markedly transform the growth inhibitory effects of Selumetinib. Our analysis of new resistance models has identified several completely novel potential mechanisms which we are in the process of validating. These studies will lead to further papers in addition those publications already reported and may contribute to the testing of new drug combinations in the clinic in the future.
Start Year 2013
 
Description AstraZeneca ERK 
Organisation University of Bath
Country United Kingdom 
Sector Academic/University 
PI Contribution We want to understand the various mechanisms by which ERK1/2 pathway-addicted tumour cells adapt and acquire resistance to the MEK1/2 inhibtor Selumetinib. We have generated a variety of human tumour cell lines with acquired resistance to the clinical candidate MEK1/2 inhibitor Selumetinib. These include cell lines in which BRAF is the driving oncogene but also those in which KRAS is the driving oncogene. We have analysed the activation state of the ERK1/2 pathway in these cells and in some cases validated the resistance mechanism. In other cases this analysis is ongoing. In some models we find that resistance is reversible upon drug withdrawal suggesting that resistant cells actually have a fitness deficit in the absence of drug. We are investigating the mechanisms that underlie this fitness deficit. For our partner (AstraZeneca/CRUK) this may allow development of rational strategies to overcome or delay resistance and thereby provide more durable drug responses. For our own basic biological interests this should provide insights into how this key cell fate signalling pathway is regulated; this may be relevant to emerging regenerative medicine protocols.
Collaborator Contribution AstraZeneca have performed a variety of Next Gen Seq analyses on samples provided by us to identify genetic and transcriptomic changes associated with resistance; these may be candidate resistance drivers. They are also performing xenograft studies to test specific hypotheses that emerge form our studies. Our collaborators at the University of Bath are investigating how the magnitude of ERK1/2 signalling can impart different tumour cell responses when Selumetinib is withdrawn from resistant cells. In a three-way collaboration between our lab, the CRUK-CI and AstraZeneca we are peforming high throughput drug combination screens to identify drugs that combine with Selumetinib to provide superior tumour growth inhibition or tumour cell death.
Impact Much of this is still early stage. However, high throughput drug screening has identified several drug combinations that markedly transform the growth inhibitory effects of Selumetinib. Our analysis of new resistance models has identified several completely novel potential mechanisms which we are in the process of validating. These studies will lead to further papers in addition those publications already reported and may contribute to the testing of new drug combinations in the clinic in the future.
Start Year 2013
 
Description AstraZeneca mTOR 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Inhibitors of mTOR promote healthy lifespan extension in model organisms by promoting autophagy and are also undergoing evaluation as a treatment for cancer. However, complete mTOR inhibition is not compatible with life. We are interested in how the mTOR pathway is remodelled during chronic exposure to mTOR inhibitors. We have generated cells that are resistant to mTOR inhibitors and examined the mTOR pathway to identify changes that underpin resistance.
Collaborator Contribution Our partners at AstraZeneca part funded a BBSRC PhD student to do this work, provided large quantities of mTOR inhibtor as an 'in kind' contribution and performed next gen sequencing and other analyses of resistant cells to probe for mechanisms of resistance
Impact The PhD student successfully completed their PhD, two papers have been published and additional work is ongoing.
Start Year 2011
 
Description CRUK CI ERK pathway 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have identified mechanisms of innate resistance to MEK inhibitors (MEKi) in human tumour cells. These mechanisms have in turn suggested drug combinations (MEKi + Xi, MEKi +Yi, etc) that should overcome innate resistance to MEK inhibitors allowing effect inhibition of the growth of tumor cells. We have tested these combinations in dozens of human cancer cell lines. The data is robust and merits further investigation, including validation in 'in vivo' mouse models
Collaborator Contribution Our partners are testing some of these drug combinations in 'in vivo' mouse models - a key pre-clinical validation step
Impact Partnership/collaboration still active and ongoing. Major, outputs (publications) still to emerge
Start Year 2014
 
Description Developing novel cell based assays to find new inhibitors the RAS-RAF-MEK-ERK pathway 
Organisation PhoreMost
Country Unknown 
Sector Private 
PI Contribution We have developed cell-based transcriptional reporter assays that allow screening in cells for novel inhibitors of the RAS-RAF-MEK-ERK signalling pathways
Collaborator Contribution Our partners have sued these cell based assays to screen for novel peptide-based inhibitors using their proprietary technology
Impact This collaboration led to a successful Innovate UK funding award between PhoreMost and the Cook lab at the Babraham Institute It has also led to a separate 3-way research collaboration between PhoreMost, the Cook lab at the Babraham Institute and Plexxikon, a structure-based drug discovery SME in California
Start Year 2017
 
Description EU LIFE Translational Research 
Organisation Austrian Academy of Sciences
Department Research Centre for Molecular Medicine
Country Austria 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Central European Institute of Technology (CEITEC)
Country Czech Republic 
Sector Charity/Non Profit 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Centre for Genomic Regulation (CRG)
Country Spain 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation European Institute of Oncology (IEO)
Country Italy 
Sector Charity/Non Profit 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Flemish Institute for Biotechnology
Country Belgium 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Friedrich Miescher Institute for Biomedical Research (FMI)
Country Switzerland 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Helmholtz Association of German Research Centres
Department The Max Delbrück Center for Molecular Medicine (MDC)
Country Germany 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Institute for Molecular Medicine Finland
Country Finland 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Lourinhã Museum
Department Gulbenkian Institute of Science
Country Portugal 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation Netherlands Cancer Institute (NKI)
Country Netherlands 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description EU LIFE Translational Research 
Organisation University of Copenhagen
Department Biotech Research and Innovation Center (BRIC)
Country Denmark 
Sector Academic/University 
PI Contribution Babraham is part of the EU LIFE Alliance of 13 top european life science institutes which collaborate in various areas to support and strengthen European research excellence. The BI Head of Knowledge Exchange & Commercialisation is a group leader in the Signalling Programme and represents BI on the Translational Research Working Group. This WG works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Collaborator Contribution The EU LIFE Translational Research Working Group works together to share best practice, promote collaborations, arrange EU LIFE scientific meetings and write policy papers.
Impact One policy paper on promoting translational research in the EU. 3 scientific meetings have been arranged so far. Other impacts are anticipated
Start Year 2013
 
Description Jean-Antoine Girault 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Public 
PI Contribution Analysis of data, and predictive modelling
Collaborator Contribution Provision of experimental datasets
Impact We analysed the differences between transcriptomes of D1 and D2 receptor-containing neurons of the basal ganglia, proposed master regulators and unravelled a new signalling system regulating neuronal identity. This is a multi-disciplinary collaboration involving experimental and computational biology.
Start Year 2016
 
Description Nick Luscombe 
Organisation University College London
Department Division of Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided data, knowledge and experience
Collaborator Contribution Training in bioinformatic techniques
Impact Publications, a number are on-going. Multi-disciplinary, biochemistry, computer modelling, bioinformatics, biological chemistry/mass spec development.
Start Year 2012
 
Description Regulation of signalling through the Ras/ERK pathway by DUSPs 
Organisation University of Dundee
Department Computer Vision and Image Processing (CVIP)
Country United Kingdom 
Sector Academic/University 
PI Contribution We are undertaking high content microscopy to assess the impact of ablating expression of dual specificity phosphatases (DUSPs) on spatiotemporal aspects of ERK signalling and resultant cell fate decisions
Collaborator Contribution Stephen Keyse's lab are generating unique DUSP null cell lines and mutant DUSP constructs
Impact Too early to assess full impacts - collaboration has only recently started.
Start Year 2017
 
Description Saez-Rodriguez ERK 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated gene expression data sets from cells exhibiting different levels of ERK1/2 signalling that drive different cell fates - cell proliferation or cell cycle arrest & senescence.
Collaborator Contribution Our partners have provided bioinformatics support and training to a PhD student who was embedded in the partner group at the EBI. This included network analysis and gene set enrichment analysis. It led to some completely new insights into how ERK1/2 signalling controls cell cycle arrest/senescence
Impact A review article has been published and a primary research paper is in preparation and will certainly lead to additional outputs
Start Year 2013
 
Description p62 phosphorylation 
Organisation University of Tromso
Department Department of Medical Biology
Country Norway 
Sector Academic/University 
PI Contribution Sharing of data; discussion of new experimental directions; experiments We have identified p62/SQSTM1 as a novel substrate of DYRK1B and DYRK2. We are investigating the role of this phosphorylation on p62 functions in proteostasis, stress responses and nutrient signalling
Collaborator Contribution Terje Johansen's lab will share reagents and expertise and perform specific experiments to define the interaction between DYRKs and p62
Impact Too soon for any specific outputs as the collaboration has only just started. However, i have visited the University of Tromso and presented two Lectures as part of a PhD training course
Start Year 2017
 
Title JSBML 
Description JSBML is a community-driven project to create a free, open-source, pure Java library for reading, writing, and manipulating SBML files and data streams. 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact Software and database developed in Java can now use a native library to read and write mathematical models encoded in SBML, the most used format in systems biology. 
URL http://sbml.org/Software/JSBML
 
Title Mathematical Modelling Ontology 
Description The Mathematical Modelling Ontology (MAMO) is a classification of the types of mathematical models used in the life sciences (for the time being), the type of variables they use, the readout that can be expected and other relevant features. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact MAMO is used to annotate mathematical models in systems biology 
URL http://co.mbine.org/standards/MAMO
 
Title SBpipe 
Description This package contains a collection of pipelines for dynamic modelling of biological systems. It aims to automate common processes and speed up productivity for tasks such as model simulation, single and double parameter scan, and parameter estimation. 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact Streamlined model identifiability and parameter estimation in systems biology modelling. 
URL https://pdp10.github.io/sbpipe/
 
Title Systems Biology Format Converter 
Description The Systems Biology Format Converter (SBFC) aims to provide a generic framework to convert a Systems Biology model format into another. Interoperability between formats is a recurring issue in Systems Biology. 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact Systems Biology software and databases can use a single conversion system to import and export a variety of formats. 
URL http://sbfc.sourceforge.net/mediawiki/index.php/Main_Page
 
Description BI School day 2017 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact NA
Year(s) Of Engagement Activity 2017
 
Description 12th International Congress of Cell Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary talk entitled "Modelling the regulation of bidirectional synaptic plasticity by allosteric calcium sensors"
Year(s) Of Engagement Activity 2016
 
Description 2016 Conference on Computational Modelling with COPASI 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk entitled "Allosteric calcium sensors in synaptic plasticity"
Year(s) Of Engagement Activity 2016
 
Description 2nd Disease Maps community meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Lecture entitled "Modelling allosteric calcium sensors: The curse of combinatorial explosion"
Year(s) Of Engagement Activity 2017
 
Description 2nd International AgedBrainSYSBIO symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk entitled "Synapses, Systems and Simulations"
Year(s) Of Engagement Activity 2016
 
Description Applied Bioinformatics in Life Sciences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary talk entitled "Modelling the regulation of bidirectional synaptic plasticity by allosteric calcium sensors"
Year(s) Of Engagement Activity 2016
 
Description BI School day 2015 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 10 of the pupils attending the Babraham Institute school day visited my lab. We gave them presentations and practicals on building and analysing networks. This included activities with Haribos and toothpicks, as well as computer based tutorials (using the software Cytoscape)
Year(s) Of Engagement Activity 2015
 
Description BI School day 2016 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact NA
Year(s) Of Engagement Activity 2016
 
Description Computational Modeling in Biology Network 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I created COMBINE to coordinate the development of standards in computational systems biology. The initiative includes several workshops a year (discussion of future standards, implementation of current standards, and end-user training), diffusion lists, social media dissemination.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
URL http://co.mbine.org
 
Description ISCB Community of Special Interest SysMod 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Recently, advances in genomics have caused bioinformatics and systems biology modeling to converge. For example, systems modeling has become more reliant on bioinformatic network inference to build models and has begun to use transcriptomics and proteomics data to train models. More communication between systems modelers and bioinformaticians is needed to further integrate these fields. In particular, more communication between systems modellers and bioinformaticians is needed to build models of whole cells, organs and organisms. The Computational Modeling of Biological Systems (SysMod) Community Of Special Interest aims at bridging the gap. Its first activity is the organisation of a Special Interest Group symposium at the annual bioinformatics conference (ISMB).
Year(s) Of Engagement Activity 2016
URL http://sysmod.info
 
Description Introduction to Networks - UTC 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I presented the notion of networks, their ubiquity, how to analyse their structure. I then focused on biological networks, their importance, how to reconstruct and analyse them.
Year(s) Of Engagement Activity 2015
 
Description Introduction to Networks - UTC 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact NA
Year(s) Of Engagement Activity 2016
 
Description Molecular mechanisms of they synapse 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk entitled "Allosteric calcium sensors in synaptic plasticity"
Year(s) Of Engagement Activity 2016
 
Description Natural Science Tripos, University of Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact I gave a course "Introduction to Modelling in Systems Biology"
Year(s) Of Engagement Activity 2017
 
Description Participated in Babraham Institute exhibit at Royal Society Summer Science Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Babraham Institute prepared an exhibit - The Ageing Clock - which exemplified aspects of our ageing research portfolio for a public audience. Tjis was selcted tp be part of the prestigious Royal Society Summer Science Exhibition and I was involved in presentign this exhbit to the Public togehter with colleagues.
Year(s) Of Engagement Activity 2018
 
Description Public feedback exercise 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The Signalling Department, in parallel with other BI departments, presented our research to a professionally selected sample of the UK public with the interntion of gaining public feedback on our institute and research.
Year(s) Of Engagement Activity 2015
 
Description School visits 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The students were enthused about the topic of my presentation and this led to dialogue and discussion about several issues including new cancer therapies, evolution of drug resistance in cancer, the use of animals in research.


Anecdotally, the institute received requests for summer placement students following this visit.
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018
 
Description Science Europe Workshop - career pathways in multidisciplinary research 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Group discussions on career pathways in multidisciplinary research. I gave a presentation entitled "The Problem of Authorship and Recognition in Systems Biology - Maintaining the Dew/Due Point"
Year(s) Of Engagement Activity 2015
 
Description Science Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Students visited the lab and undertook small lab-based proejcts supervised by students/post-docs and myself. I explained the research that we do and discussed ethical issues such as the use of animals in research.
This precipitated excellent discussion and dialogue.

We received excellent feedback from the schools involved and requests for further outreach activities
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
 
Description Teaching Networks and Pathways, Cambridge Universtity Part III Systems Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Around 40 students of the Cambridge University Part III Systems Biology attended my course on Networks and biochemical pathways. The course was accompanied by a tutorials on reconstructing and analysing networks as well as a journal club, where students analysed relevant publications.
Year(s) Of Engagement Activity 2015
 
Description Teaching Networks and Pathways, Cambridge Universtity Part III Systems Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact NA
Year(s) Of Engagement Activity 2016
 
Description Teaching modelling at Gebze Technical University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact NA
Year(s) Of Engagement Activity 2017
 
Description Visits by Teachers 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I hosted two 6th form Biology teachers (one PhD trained, the other MSc trained) who were visiting my Institution during Half Term to update their knowledge as part of their CPD
Year(s) Of Engagement Activity 2016