Systems Biology analysis of biological timers and inflammation

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences

Abstract

As we get older our immune system tends to get weaker and it becomes increasingly difficult to shake off diseases. At the same time we tend to develop arthritis and other auto-immune diseases which are localised instances of uncontrolled inflammation. In this grant application our multidisciplinary team of scientists consisting of physiologists, biologists, mathematicians and computer scientists aim to look at a very important signalling system NF-kappaB. This system plays an important role in stress and the immune responses and determines the fate of cells in the body, which is essential for general health and wellbeing. We will use a combined experimental and mathematical approach to analyse integrated systems that control NF-kappaB signalling in normal cells and tissues.
We found that NF-kappaB carries signal information in the timing of its movements between the nucleus and cytoplasm. The timing of these movements determines which genes are switched on. We now wish to understand how this key process of NFkappaB signalling is controlled through normal life. How is it controlled by the cell division cycle, and how is it controlled by the sleep-wake cycle of the 24 h circadian clock.
Recently, we have found that the speed of the oscillations in the NF-kappaB signalling system are very temperature sensitive in the physiological and fever range between 35 and 40 degrees C. This also appears to markedly change the pattern of which genes are switched on or off. Our work so far has been in cell lines grown in the laboratory and we now wish to investigate NF-kappaB signalling in normal cells taken from transgenic mice that have fluorescently labelled NF-kappaB proteins. We will use these cells to determine the NF-kappaB response to temperature, a range of physiological stimuli including glucocorticoids (which are often used in inflammatory treatment), to screen small molecule drugs to find ones that modulate the response and to study the quantitative relationships with the cell cycle and the circadian clock. The data from these experiments and others published in the literature will be used to build integrated mathematical models that can predict important aspects of cell, tissue and animal physiology relevant to understanding the maintenance of a healthy organism and how this may change with age.
Key aims will be to understand how the clock and cell cycle together affect the timing and level of NF-kappaB signalling and which target genes are switched on. One of the NF-kappaB family of proteins, p105 encoded by the NFkB1 gene, has been found to cause faster ageing in mice when this gene is missing (Mann and von Ziglnicki, personal communication). We wish to investigate whether changes in NF-kappaB dynamics are involved in this ageing condition. Therefore, we will make a BAC reporter for p105 with fluorescent fusions at either end of the protein.
We are an ideal team to perform this work, because we have complementary interdisciplinary skills in cell imaging, image analysis, molecular cell biology, physiology, genomics, bioinformatics and mathematical modelling. A core part of the team has an excellent track record of working together to analyse the NF-kappaB signalling system. In addition, this new project brings in new team members with considerable expertise in animal physiology, circadian clocks and endocrinology.

Technical Summary

We will develop a new quantitative understanding of coordinated inflammatory signalling in primary cells & tissues. We previously showed novel single-cell dynamics & function of the key inflammatory NF-kappaB signaling system in cell lines. This work has established a central hypothesis that coupling between multiple dynamic systems may allow different signals to be coordinated to ensure accurate & appropriate cell & tissue inflammatory responses. A key aim of this project is to understand process coordination between the NF-kappaB, circadian clock & cell cycle systems. Work will include 1) exploitation of transgenic models for NF-kappaB analysis system (using RelA & IkappaBalpha fluorescent BAC reporter mice) & the coupling with the circadian clock (cross with the Per2 luciferase reporter mice). 2) Analysis of the coupling between NF-kappaB, circadian clock & cell cycle in cell lines, primary cells & tissues using dynamic cell & single molecule imaging, quantitative proteomic & gene expression assays. 3) Perturbation analyses of system coordination using physiological stimuli, temperature, stimulation with glucocorticoids, disruption of clock (knockout & fast clock mutants) & a chemical screen to identify new agents that modulate NF-kappaB dynamics. 4) A key collaboration will be initiated with D. Mann & T. von Ziglnicki (Newcastle) to analyse NF-kappaB dynamics in NFKB1 KO that show an ageing phenotype. The theoretical work will produce new multi-scale deterministic & stochastic models to enable accurate predictions of temporal gene responses for a given input, thus providing new understanding of process coordination during inflammation. Modelling & experimental approaches will be used iteratively to direct experimental design. Our key aim is to provide new insights for understanding coupled biological systems that underlie the control of inflammation in cells & tissues in healthy & ageing organisms.

Planned Impact

The application of systems biology offers great potential for a better understanding of cell signalling and decision-making pathways. This in turn creates the opportunity for the identification of better drug targets and more efficacious modes of treatment of disease. This application is relevant to important processes in human and animal disease. In inflammation and innate immunity, NF-kappaB is a critically important regulator. The clock and cell cycle are important regulatory timing systems that control fundamental aspects of biology. This project is important for applied research and is of relevance to healthcare and to the pharmaceutical industry.
In this respect we have strong support for this project from GlaxoSmithKline (GSK, see letter from S. Farrow). They will assist us in conducting a new screen for small molecules that modulate the dynamics of NF-kappaB signalling (providing £20k pa of in kind support). GSK are also substantially supporting other work in the labs of A. Loudon and D. Ray. Until recently, M. White had an established collaboration with AstraZeneca (AZ) through Dr J. Unitt, who was a co-author on our major NF-kappaB papers. With the closure of AstraZeneca Charnwood this collaboration was put on hold. Recently AZ and GSK have each jointly funded the new £15m Manchester Collaborative Centre for Inflammation Research (MCCIR). It has been agreed by all involved that the present project would be affiliated to MCCIR. Following the likely appointment of a new Director in the next few weeks, it is anticipated that details of available in-kind support for the current project from the MCCIR will be formally agreed.
The major technologies being used in this project are based on bio-imaging. This is an important and currently growing area. We have close relationships with instrumentation companies and in particular with Carl Zeiss and Hamamatsu Photonics with whom MW has collaborated for 16 and 20 years respectively. This involves the loan and testi of equipment and the exchange of ideas, for new developments in microscopy and detection. Both companies will sponsor the project through support for the microscopy training courses in years 1,3 and 5 (the first course will be joint with the last SABR course thus saving on costs) The companies will provide speakers for the course from Germany and Japan, the loan of demonstration equipment and financial support. While the course is focused on providing training for the staff on the SABR project, places have been made available to staff on other systems biology projects from around the country. Representatives of each of the instrumentation companies are on the scientific advisory board for the BBSRC SABR project.
The use of microscopy generates movies and images that are colourful and visual. They represent an excellent resource for the development of public understanding of science. MW has given lectures at Public Understanding of Science meetings (e.g. ASE lecture in 2008). In 2006 a group from the CCI led by MW and DS, presented an exhibit entitled "The Language of Cells" at the Royal Society exhibitions in London, Glasgow and at Science Day at Buckingham Palace. The whole group are very keen apply to exhibit at future Royal Society exhibitions and this project may well give us a useful theme from which to develop a new exhibit. This offers a specific opportunity and we will seek others through talking to schools and other groups. When publicity of outcomes from this project are important, we will engage with the University of Manchester Press Office to coordinate this. We have good experience of media publicity and have previously worked with the BBSRC Press office in publicising high impact publications.

Publications

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Bagnall J (2015) Quantitative dynamic imaging of immune cell signalling using lentiviral gene transfer. in Integrative biology : quantitative biosciences from nano to macro

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Diamond C (2016) Investigating IL-1ß Secretion Using Real-Time Single-Cell Imaging. in Methods in molecular biology (Clifton, N.J.)

 
Description We have made and characterised transgenic mice that allow us to see movements and changes in the gene expression of NF-kB proteins in living primary cells and tissues (fluorescent protein fusions with IkBa, RelA, RelB, c-Rel and a TNFa-Luciferase reporter line). We have observed that the NF-kB signalling system shows oscillatory movement of the NF-kB transcription factors between the cytoplasm and nucleus in a variety of different cell types including fibroblasts, cartilage and gut organoids. The frequency of these movements varies between different cells and in response to different stimuli. This considerably extends previous work that was performed on cell lines.
- Temperature regulates NF-kB dynamics through a mechanism involving the feedback inhibitor A20. Changes in temperature give a more subtle change in global gene expression with a specific set of genes changing their expression profile (different to the effect of changing NF-kB frequency via pulsing with TNFa (Harper, PNAS)
- Aspirin and diclofenac also change both NF-kB dynamics and the riming of A20 gene expression. (Harper, in prep)
- The NF-kB response encodes information through both NF-kB dynamics and subunit phosphorylation / differential dimer formation. This has been analysed through mutual information analyses. The profile of a small number of genes can accurately predict the signal context of the cell, suggesting the system can transfer multiple bits of information. (Minas, PNAS submitted)
- Processing of the p105 and p100 NF-kB subunits releases the p50 and p52 subunits. This process involves two levels of control. We have used a novel real-time FRET assay to identify that in p105 a GSK3beta phosphorylation site regulates the interaction between the IkB and Rel parts of p105. This in turn permits phosphorylation and ubiquitin-dependent processing. (Jones, in prep)
- In primary cells, the oscillations in NF-kB vary in a context-dependent way from single phases of nuclear translocation to cycles with different timing. In gut organoids faster oscillations are observed, while cartilage cells show more synchronous responses to IL1b.
- The timing of NF-kB responses in cartilage is regulated by the circadian clock and glucocorticoids on a mechanism involving p38 and DUSP proteins.. (Borysziewicz in preparation)
Macrophages express local high concentration pulses of TNFa to activate NF-kB in target cells via a hit and run mechanism suggesting most often that this will generate single phases of NF-kB translocation (Bagnell et al., Science Signaling)
Pulsing of TNFa at different frequencies shows that there is a variable delay with a median of ~60 minutes before cells are ready to respond again. This delay is A20 dependent. (Adamson et al., Nat. Comm.)
Cells that show less robust oscillations (eg. HeLa cells) tend to express higher levels of A20. Lowering these levels in HeLa cells gives robust oscillations in response to TNFa (Lam et al,.)
Levels of feedback gene expression are very low. For example in unstimulated SK-N-AS there is an average of ~0.2 molecules of A20 RNA per cell at any moment of time. This suggests key questions about stochasticity and robustness. (This work benefits from quantitative RNAFISH analysis and FCS protein analysis).
The alternative pathway NF-kB protein oscillates with independent amplitude to RelA and can have independent timing showing it is an independent oscillator. (McNamara et al., in prep)
Alongside this work new stochastic tools have been developed to discern transcription dynamics and on and off periods.
Exploitation Route The work provides generic tools and mathematical models for understanding inflammatory processes in living animals. Tis can identify new targets for modulation of signal dynamics.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The work has been presented at multiple international meetings and involves collaborations with instrumentation companies and a major pharmaceutical company Work from the project has been presented in schools and museums.
First Year Of Impact 2013
Sector Education,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Appointed to Pool of Experts for BBSRC Panels, 2012-2013.
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BBSRC Bioscience for Industry Committee (single meeting for presentation)
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BBSRC Panel: Enabling Theme 2, the Exploiting New Ways of Working Strategy Panel (ENWW)
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BBSRC Strategic Tools and Resources Development Fund (sTRDF) Panel
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BBSRC Strategy Meeting
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description External Reviewer for FRISYS-ZBSA (Zentrum fur biosystemanalyse), Freiberg, Germany, 26th May 2011.
Geographic Reach Asia 
Policy Influence Type Membership of a guidance committee
 
Description German Virtual Liver Scientific Advisory Board (42m euros programme )
Geographic Reach Asia 
Policy Influence Type Participation in a advisory committee
URL http://www.virtual-liver.de/wordpress/en/media/handling-biological-complexity-using-systems-approach...
 
Description Invited to attend Research Sponsors' Consultation Meeting (BBSRC &MRC) on Imaging for the biological and biomedical sciences, 14 May 2012.
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description MRC Microbiome
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description MRC Systems Immunology
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description MRC/BBSRC New Microscopy Initiative
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Member and deputy chair of UKRI Future Leaders Fellowship panel (sift and interview)
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://www.ukri.org/funding/funding-opportunities/future-leaders-fellowships/
 
Description Member of BBSRC LoLa oanel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://bbsrc.ukri.org/funding/filter/lola/
 
Description Member of BBSRC Research Equipment Initiative (REI) Review Panel
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of BBSRC Site visit to Imperial Centre for Systems Biology
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of BBSRC Site visit to Oxford Centre for Systems Biology
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of BBSRC Tools and Resources Development Fund Panel, Feb 2012.
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of BBSRC/EPSRC TDRI Panel
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of MRC Doctoral Training Panel
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of MRC Human Cell Atlas Panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://mrc.ukri.org/funding/browse/hca/human-cell-atlas/
 
Description Member of MRC Methodology Panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://mrc.ukri.org/about/our-structure/research-boards-panels/methodology-research-programme-panel...
 
Description Member of MRC Population and System Medicine Board, 1 April 2012 - 1 April 2016
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Member of MRC Sjills Fellowship Panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Appointment of MRC skills dellowships and award of institutional skills dellowships grants to develop the careers and training of early career researchers
URL https://mrc.ukri.org/skills-careers/fellowships/skills-development-fellowships/
 
Description Member of joint research council tecnology touching life advisory group
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://www.ukri.org/research/themes-and-programmes/technology-touching-life/
 
Description Membership of BBSRC Interdisciplinary Systems Biology Strategy Committee
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
 
Description Roving panel member for EPSRC CDT interviews
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://epsrc.ukri.org/skills/students/centres/2018-cdt-exercise/
 
Description Wellcome Trust/Wolfson Capital Awards in Biomedical Sciences Committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description (W Muller, MW, D Jackson, S Schreiber, T Hofer, D Rand, C Troutwein, J Rhodes, M Pierik, N Schpigel, VM dos Santos, A Kel, L Ferguson, B Fuchs). Systems medicine of chronic inflammatory bowel disease.
Amount £2,583,208 (GBP)
Funding ID 305564 
Organisation Systems Medicine of Chronic Inflammatory Bowel Disease 
Sector Public
Country European Union (EU)
Start 12/2012 
End 11/2017
 
Description A "Molecular Imaging (FLIM/FCS) toolbox" to investigate molecular interactions and activation in super-resolution and widefield mode
Amount £255,000 (GBP)
Funding ID 202923/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2016 
End 10/2020
 
Description A*Star PhD Studenship
Amount £15,000 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2021
 
Description An upright confocal microscope for multidisciplinary research
Amount £282,781 (GBP)
Funding ID BB/R014361/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2018 
End 04/2019
 
Description Capital clinical infrastructure for single cell genomics
Amount £4,900,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2015 
End 03/2020
 
Description Development of novel luciferases for real-time monitoring of protein secretion.
Amount £117,309 (GBP)
Funding ID BB/K013882/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2013 
End 06/2014
 
Description EPSRC Responsive Mode
Amount £356,217 (GBP)
Funding ID EP/P019811/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2020
 
Description Exploring the link between inflammation and endocrine signalling in the hypothalamus: the role of neuronal dynamics in healthy ageing.
Amount £30,346 (GBP)
Funding ID BB/L026902/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2014 
End 03/2015
 
Description ISSF Research Grant
Amount £35,604 (GBP)
Funding ID 097820/Z/11/B 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2013 
End 09/2014
 
Description ISSF Research Training Grant
Amount £2,158 (GBP)
Funding ID 097820/Z/11/B 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 09/2014
 
Description ISSF Research grant
Amount £12,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2016
 
Description MRC Discovery award: "Capacity Building in Single Cell Inflammation Discovery: Developing the Next Generation of Scientists"
Amount £750,000 (GBP)
Funding ID MC_PC_15072 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 09/2017
 
Description MRC project grant
Amount £675,328 (GBP)
Funding ID MR/P011853/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2017 
End 02/2020
 
Description Quantification of protein dynamics driving the circadian clock
Amount £610,426 (GBP)
Funding ID BB/P017347/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 12/2017 
End 11/2020
 
Description Temporal manipulation of genetic circuits in single cells
Amount £122,019 (GBP)
Funding ID BB/P027040/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 09/2018
 
Description Wellcome Trust 4-year PhD Programme in Quantitative and Biophysical Biology
Amount £2,555,000 (GBP)
Funding ID 108867/B/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 01/2023
 
Description programme grant
Amount £2,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 08/2022
 
Title Development of fluorescence correlation spectroscopy for protein quantification and interaction measurement 
Description Tool based on confocal microscopy for measurement of absolute fluorescent protein concentration and measurement of protein dissociation constants in single living cells. They method involves a combination of experimental measurement and mathematical analysis of the data. Further development to consider use with light sheet microscope in collaboration with Zeiss. 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Papers published. Collaboration with Carl Zeiss. 
 
Title Data from: Dynamic NF-?B and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation 
Description  
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
 
Title Secretome analysis of macrophage signalling 
Description Secretome analysis of RAW264.7 cells in response to TLR4 agonist 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Resources for use to other researchers 
URL http://www.ebi.ac.uk/pride/archive/projects/PXD001905
 
Title Transcriptome analysis of macrophage signalling 
Description Gene expression analysis of TLR4 signalling in RAW 264.7 macrophage cell line 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Incasing depth of knowledge 
URL https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3155/
 
Description Carl Zeiss 
Organisation Carl Zeiss AG
Country Germany 
Sector Private 
PI Contribution We have advised Zeiss on trends in bioimaging since 1996. We have provided new data and tested prototype equipment. We have spoken at Zeiss organised meetings. We have given them an opportunity to display Zeiss equipment at our training courses. We have organised symposia that have been supported by Zeiss. We have held expert discussion meetings to review microscopy trends that have involved senior Zeiss staff
Collaborator Contribution Zeiss have made a cash contribution to training courses (received) of £16,250. Zeiss estimate of total value of in-kind staff time for collaboration, training courses and other meetings (including visits of teams from Germany) ?25,000. In addition, Zeiss have also committed over £30,000 in cash and ~£80000 in in kind staff for future training meetings and collaborative visits. Zeiss helped to design the new Systems Microscopy Centre in Manchester and made a 45% discount (value ?350k) for the purchase of equipment in 2011. Zeiss are a formal MICA partner on both Liverpool and Manchester awards from the MRC/BBSRC New Microscopy Initiative. In the award to Manchester they have made a contribution of £614,314 in staff time, development costs and equipment contribution. This involves FCS (developed during this project), luminescence fluorescence imaging, light sheet microscopy and SOFI super-resolution imaging. More recently Zeiss have made a further contribution to our new clinical single cell centre. This includes over £400k in equipment discounts and £25k in cash contribution to training and symposia. Over the years the Zeiss contributions have included them helping us with public understanding of science exhibitions where they loaned equipment, provided support for professional poster preparation and used their delivery services to transport our exhibit materials and equipment to the exhibition venues. This included an exhibition in Buckingham Palace in 2006. Zeiss have sponsored 2-3 meetings per year in Manchester. In 2016 this included a session on light sheet imaging and a session on new confocal imaging technologies. In 2017 they have sponsored an image analysis daya and will sponsor a single cell biology workshop.
Impact Annual training courses MICA collaborative MRC grant MICA collaboration on new single cell centre The relationship with Zeiss has been two way. We have been given the opportunity to be early adopters f new technology and to feedback idease for improvement. We receive very favourable deals on microscope purchases and maintenance contracts. Specific areas of successful collaboration lie in improvements to higher throughput live cell imaging using the confocal microscopes; optimisation of truly dark microscopes for quantitative luminescence imaging and the development of FCS. Multiple workshops organised (2-3 per yeat)
 
Description Collaboration with AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have discussed many aspects of our research with the staff from AstraZeneca, allowing them to help us to develop our research further. We also tested some candidate drugs. We have taken part in joint meetings and presented several seminars at AstraZeneca
Collaborator Contribution We had a longstanding collaboration with AstraZeneca who advise on a number of projects and have made facilities and reagents available to us. As a result of this one AstraZeneca employee was a co-author on our Science paper by Ashall et al. (19359585). This collaboration closed following the closure of the AstraZeneca Charnwood site. Recently we have resetablished this collaboration and in the next few months a senior AstraZeneca employee plans to spend time in our lab learning imaging techniques.
Impact Ashall et al (19359585)
Start Year 2006
 
Description Collaboration with Cancer Research Technologies 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Running of drug screen for novel NF-kB timing modulators.
Collaborator Contribution Assistance with design of the screen
Impact Early stage of collaboration
Start Year 2015
 
Description Collaboration with Glaxo Smithkline 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We are contributing imaging expertise and knowledge of NF-kappaB signalling
Collaborator Contribution GSK are contributing in kind resources and expertise to assist with a new drug screen for compounds that alter NF-kappaB dynamics.
Impact We are only just at the start of this collaborative stage of the project. We are about to discuss detailed arrangements and agreements
Start Year 2013
 
Description Collaboration with Intitute of virus research, University of Kyoto 
Organisation University of Kyoto
Department Institute for Virus Research
Country Japan 
Sector Academic/University 
PI Contribution This involved a visit by a postdoc to receive specific training from Prof. Kageyama's laboratory in optogenomics. The grant provided funds for this and one member of staff visited Kyoto for training.
Collaborator Contribution Professor Kageyamas lab provided training n optogenetics. This allowed the expertise to be brought back to Manchester and permitted new project planning
Impact This was a short training visit which achieved the aim of training and technology transfer. One person was trained and reagents and expertise were transferred from Kyoto to Manchester. Both laboratories work on biological timing so there was also additional benefit in shared knowledge.
Start Year 2016
 
Description Collaboration with University of Liverpool 
Organisation University of Liverpool
Department Institute of Integrative Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution of data and intellectual input on shared BBSRC grant. Collaboration on student training.
Collaborator Contribution Contribution of data and intellectual input on shared BBSRC grant. Collaboration on student training. (This was a continuing collaboration following move of M. White from Liverpool to Manchester)
Impact Multi-disciplinary - including mathematics, translational medicine and proteomics.
Start Year 2010
 
Description Collaboration with University of Warwick 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution We have shared data and made visits to Warwick to discuss the collaboration.
Collaborator Contribution We have established a strong systems biology collaboration with the Systems Biology Department in Warwick (particularly with Prof. D. Rand). They have become our principal mathematics collaboration and contributed very significantly to our recent Science paper (Ashall et al.,) and other papers submitted or in preparation. This collaboration included the Warwick group (T. Brettschneider) using their own funds to assist us in the development of cell imaging programs through their employment of a post-doc. We also have collaborated over student training.
Impact This multidisciplinary collaboration led to the award of the £5m BBSRC SABR grant between warwick, Liverpool and Manchester. This directly arose from this collaboration with the Warwick group assisting with the predictive modelling work. The collaboration supported the Science paper by Ashall et al., (19359585) In 2010 through more distantly related work, a £1.4m Wellcome trust Programme grant was awarded to Manchester and Warwick. In 2013 a further directly related £3.6m BBSRC sLOLA grant was awarded to Manchester and Warwick.
Start Year 2007
 
Description Hamamatsu Photonics 
Organisation PMT Hamamatsu Photonics K.K.
Country Japan 
Sector Private 
PI Contribution We have advised Hamamatsu on trends in bio-imaging for 20 years. We have provided new data and tested prototype equipment. We have given them an opportunity to display their equipment at our training courses.
Collaborator Contribution They have loaned us equipment and provided privileged discounts for almost 20 years (in kind value well over £100k). They have advised us on new emerging technology. They have assisted by providing staff for our training courses (recent in kind value calculated as £50k. They have provided £10k in cash towards training courses since 2008. A further £4k in cash and £10k has been committed to future training courses.
Impact Annual training courses
 
Description BIOMS Symposium 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote Lecture. BIOMS Symposium 2018, BioQuant, University of Heidelberg, October, 2018. Title: Multiplexing information flow through dynamic signalling systems
Year(s) Of Engagement Activity 2018
 
Description Invited Lecture, Oberwolfach Meeting June, 2017. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Invited Lecture, Oberwolfach Meeting on Reaction Networks and Population Dynamics, June, 2017.
Year(s) Of Engagement Activity 2017
 
Description Invited Spring School Lectures at CompSysBio Spring School. Aussois, France. March 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Two Invited Spring School Lectures. Information and Decision-Making in Dynamic Cell Signalling.
Year(s) Of Engagement Activity 2017
URL https://project.inria.fr/compsysbio2017/
 
Description Mini-symposium on Multi-scale Mathematical Models in Endocrinology. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Lecture, ECMTB 2018 Stochastic transcriptional dynamics and spatial signalling for the prolactin gene in single cells and tissue. Mini-symposium on Multi-scale Mathematical Models in Endocrinology.
Year(s) Of Engagement Activity 2018
 
Description School visit (Liverpool Life Sciences, University Technical College) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Liverpool Life Sciences UTC is the first school in the UK specialising in Science and Health Care for 14 to 19 year olds. Talk at Liverpool Life Sciences UTC conference on "How Organisms Age"
Year(s) Of Engagement Activity 2016
 
Description School visit, (Manchester Grammar School) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Dean Jackson Feb 2017, Science Fair judge for student projects
Year(s) Of Engagement Activity 2017
 
Description Schools University Partnership Initiative event representing medical research in Faculty of Life Sciences, Manchester linked to Cancer and Ageing. 
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 Dean Jackson - General outreach to schools
Year(s) Of Engagement Activity 2016
 
Description school visit (Xaverian College) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Dean Jackson - STEM ambassador
Year(s) Of Engagement Activity 2016