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.
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 testing 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.
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 testing 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.
Organisations
- University of Manchester (Lead Research Organisation)
- AstraZeneca (United Kingdom) (Collaboration)
- PMT Hamamatsu Photonics K.K. (Collaboration)
- Carl Zeiss AG (Collaboration)
- National University of Singapore (Collaboration)
- Cancer Research UK (Collaboration)
- University of Kyoto (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- University of Liverpool (Collaboration)
- GlaxoSmithKline (United Kingdom) (Project Partner)
- Carl Zeiss (United Kingdom) (Project Partner)
- Hamamatsu Photonics (United Kingdom) (Project Partner)
Publications

Adamson A
(2016)
Signal transduction controls heterogeneous NF-?B dynamics and target gene expression through cytokine-specific refractory states.
in Nature communications


Assas MB
(2017)
Anti-inflammatory effects of infliximab in mice are independent of tumour necrosis factor a neutralization.
in Clinical and experimental immunology

Bagnall J
(2018)
Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation.
in Science signaling

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

Bagnall J
(2020)
Gene-Specific Linear Trends Constrain Transcriptional Variability of the Toll-like Receptor Signaling.
in Cell systems

Brignall R
(2017)
Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.
in Journal of immunology (Baltimore, Md. : 1950)

Caballero I
(2017)
Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol.
in Scientific reports

Daniels M
(2016)
Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models
in Nature Communications

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 | BBSRC Strategy Meeting |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Description | Member and deputy chair of UKRI Future Leaders Fellowship panel involvement in 3 sift and 2 interview committees from 2018 - 2021) |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Impact | Award of Fellowships for training of future leaders |
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 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 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 to March 2020 |
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 | 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 | bbsrc fellowships strategy workshop |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
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 | United Kingdom |
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 lattice lightsheet microscope for imaging highly dynamic processes in living cells and organisms. |
Amount | £463,177 (GBP) |
Funding ID | BB/S019286/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 10/2020 |
Description | A*Star PhD Studenship |
Amount | £15,000 (GBP) |
Organisation | University of Manchester |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2017 |
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 | 04/2018 |
End | 04/2019 |
Description | Capital clinical infrastructure for single cell genomics |
Amount | £4,900,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2015 |
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 | 04/2013 |
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 | Public |
Country | United Kingdom |
Start | 03/2017 |
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 | 03/2014 |
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 | 09/2015 |
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 | Public |
Country | United Kingdom |
Start | 08/2016 |
End | 09/2017 |
Description | MRC project grant |
Amount | £675,328 (GBP) |
Funding ID | MR/P011853/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
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 | 08/2017 |
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 | Public |
Country | United Kingdom |
Start | 08/2017 |
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. IN 2021-22 they provided support for the traing of tw PhD students including firect training, access to microscopy facilities and funds to attend an external course (delayed by Covid to September 2022) |
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 A star institute Singapore |
Organisation | National University of Singapore |
Country | Singapore |
Sector | Academic/University |
PI Contribution | Collaboration to supervise a PhD student through shared four year PhD programme. Student working in Singapore Sep 2021-Sep 2023 and in Manchester Sep 2020- to Sep 2021 and Sep2023 to Sep 2024. Aim is to develop tools to better understand the role of A20 regulation in NF-kappa B signalling dynamics and function. his has expanded to include processes involved in the control of apoptosis in response to TNFalpha. |
Collaborator Contribution | Hosting student for two years from Sep 2021 to Sep 2023. Collaborative work involving weekly meetings. hey have provided expertise in novel upstream signalling processes |
Impact | This project involves direct collaboration and training of a student. As such it is interdisciplinary involving molecular cell biology, bioinformatics and links with mathematical modelling. Planned joint publications. |
Start Year | 2020 |
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 | Pump priming research |
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 | Due to changes of staff in the company the originally planned collaboration was not possible. Other routed were found. |
Start Year | 2013 |
Description | Collaboration with Institute of ageing and chronic disease Liverpool |
Organisation | University of Liverpool |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in NF-kappa B signalling, microscopy and systems biology, We have helped in the characterisation of new protein structures involving the NF-kappaB protein p52 in embryonic stem cells. Other stem cell and structural biology groups in Manchester havenow become associated with this collaboration |
Collaborator Contribution | Hosting student who is jointly supervised. Expertise in developmental biology. |
Impact | We have charactrised which members of the NF-kappaB family of proteins are expressed in early development. We discovered novel structures in embryonic stem cells - large rods and rings which can be several microns in size. They are made up of / include a key enzyme in purine biosynthesis, 2 and the p52 NF-kB protein. They are dynamic and disappear on ESC differentiation, inhibition of nuclear export or knockdown of p52/p100. , We are investigating their role and the possibility that these structures are previously uncharacterised regulators of differentiation and cell division. This collaboration involves a PhD student who is jointly supervised and therefore the collaboration includes training. We are planning funding applications to investigate the function of these structures and the structural biology that underlies their formation. this may be important for understanding how pluripotence is maintained and how ESCs progress to the first differentiated cell division. This therefore has fundamental cell biology applications and potential relevance to stem cell technologies such as IPSC generation. |
Start Year | 2021 |
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 | 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 | Colloquium. "The circadian clock: using Maths to understand how a complex dynamical system controls our health and survival." University of Porto, Portugal. January 2020. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk for a broad audience on the health implications associated with the circadian clock. |
Year(s) Of Engagement Activity | 2020 |
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 | Invited lecture to Sleep Annual Meeting, Houston |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Online invited talk . TimeTeller: a New Tool for Precision Circadian Medicine and Cancer Prognosis. Sleep 2021 Annual Meeting, Houston, June 2021. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.sleepmeeting.org/ |
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 |