MICA: Finding new treatments for failed resolution of inflammation using zebrafish models.
Lead Research Organisation:
University of Sheffield
Department Name: Infection Immunity & Cardiovasc Disease
Abstract
Neutrophils are a type of white blood cell that are important in fighting infection and healing wounds (in a process called inflammation). We know that neutrophils need to be removed when their job is done or they can cause damage. The mechanisms of neutrophil removal are particularly important in a delicate organ such as the lung where failure can mean permanent lung damage as is seen in Chronic Obstructive Pulmonary Disease (COPD), a common disabling disease with no cure. We do not understand how neutrophils know when the job is done and how this translates into signals to remove neutrophils from their place of work - the inflammatory site. In my lab, I have developed tools in zebrafish that allow me to see neutrophils as they fight infection, heal wounds and importantly as they are removed during healing (or "resolution") of inflammation. These zebrafish can be genetically modified to express glowing (fluorescent) proteins that label neutrophils or to change the genes controlling inflammation. This allows us to get a much better understanding of the processes and controls of inflammation resolution. With these models, we have seen how neutrophils can be removed in 2 ways, by moving away from the site of inflammation or by dying there and being removed by another type of immune cell (macrophages).
In this programme, I propose to use zebrafish models and human neutrophils to understand the signals keeping neutrophils at sites of inflammation, which I call "retention signals". I have identified a drug that works by causing neutrophils to leave sites of inflammation and I will investigate how this changes the retention signals that neutrophils use to keep them at inflammatory sites. I will then study the downstream signals within neutrophils that act to turn these signals into changes in behaviour of the neutrophils. From recent studies in my lab, I have identified two important pathways that might be key regulators of retention signalling. The first is an enzyme, Serum and Glucocorticoid regulated kinase-1 (SGK1) that seems to act to retain living neutrophils at sites of inflammation. I will explore the potential of this kinase and related molecules to control inflammation resolution. Since this is a good drug target, this aim will be explored in collaboration with GlaxoSmithKline who are working with me to identify drug candidates targeting this molecule. Finally, a gene called Kalirin was identified in a genetic screen in my lab as a regulator of inflammation resolution. Kalirin is a protein normally controlling the direction of nerve cell growth, but it is present in neutrophils where it might control neutrophil movement. I will explore the possibility that Kalirin is involved in retention signalling and see whether it might be a suitable target for drug discovery.
Taken together these approaches will uncover new aspects of the control of inflammation resolution and identify a number of targets for drug discovery. I hope this will ultimately find new ways to treat inflammatory diseases.
In this programme, I propose to use zebrafish models and human neutrophils to understand the signals keeping neutrophils at sites of inflammation, which I call "retention signals". I have identified a drug that works by causing neutrophils to leave sites of inflammation and I will investigate how this changes the retention signals that neutrophils use to keep them at inflammatory sites. I will then study the downstream signals within neutrophils that act to turn these signals into changes in behaviour of the neutrophils. From recent studies in my lab, I have identified two important pathways that might be key regulators of retention signalling. The first is an enzyme, Serum and Glucocorticoid regulated kinase-1 (SGK1) that seems to act to retain living neutrophils at sites of inflammation. I will explore the potential of this kinase and related molecules to control inflammation resolution. Since this is a good drug target, this aim will be explored in collaboration with GlaxoSmithKline who are working with me to identify drug candidates targeting this molecule. Finally, a gene called Kalirin was identified in a genetic screen in my lab as a regulator of inflammation resolution. Kalirin is a protein normally controlling the direction of nerve cell growth, but it is present in neutrophils where it might control neutrophil movement. I will explore the possibility that Kalirin is involved in retention signalling and see whether it might be a suitable target for drug discovery.
Taken together these approaches will uncover new aspects of the control of inflammation resolution and identify a number of targets for drug discovery. I hope this will ultimately find new ways to treat inflammatory diseases.
Technical Summary
Diseases of failed inflammation resolution such as COPD are major causes of morbidity and mortality. Currently no therapies target the key effector cell, the neutrophil, to drive inflammation resolution. Targeting neutrophil recruitment leaves tissues unprotected against infection, and new approaches are needed to remove unwanted neutrophils without impacting host defence. We are in the midst of a revolution in neutrophil biology, in which neutrophils are recognised to be more long-lived, with active roles in programming adaptive immunity and regulating immune homeostasis. Neutrophils are now recognised to have a number of potential fates in addition to apoptosis. Neutrophils can reverse transmigrate back into the circulation in humans and mice, they can be lost into exudates in the mammalian lung or they can reverse migrate within tissues to dissipate the inflammatory burden - shown in zebrafish and with human neutrophils.
I hypothesise that neutrophils are retained at inflammatory sites by "retention signals" that delay reverse migration, and that neutrophil sensitivity to these signals is mediated through a pathway requiring Serum and Glucocorticoid-regulated Kinase-1 (SGK1) and Kalirin, providing a series of new targets for drug discovery. In this Programme, I will identify the nature of retention signals and how these overlap with survival signals, then explore the molecular mechanism of action of Tanshinone IIA (identified by drug screening in my lab) which drives reverse migration. I will define the functional neutrophil kinome and exploit novel kinase inhibitors and kinase targets for the selective removal of inflammatory neutrophils, using SGK1 as a prototypic downstream signal important in retention signalling. Finally, I will define the role of Kalirin (identified by genetic screening in my lab), as a regulator of neutrophil retention signalling.
I hypothesise that neutrophils are retained at inflammatory sites by "retention signals" that delay reverse migration, and that neutrophil sensitivity to these signals is mediated through a pathway requiring Serum and Glucocorticoid-regulated Kinase-1 (SGK1) and Kalirin, providing a series of new targets for drug discovery. In this Programme, I will identify the nature of retention signals and how these overlap with survival signals, then explore the molecular mechanism of action of Tanshinone IIA (identified by drug screening in my lab) which drives reverse migration. I will define the functional neutrophil kinome and exploit novel kinase inhibitors and kinase targets for the selective removal of inflammatory neutrophils, using SGK1 as a prototypic downstream signal important in retention signalling. Finally, I will define the role of Kalirin (identified by genetic screening in my lab), as a regulator of neutrophil retention signalling.
Planned Impact
The mechanisms regulating inflammation resolution are of fundamental importance in immunology. Very few targets with critical roles in inflammation resolution have been identified to date. The discoveries from this project will therefore significantly enhance the knowledge economy with new scientific advancement, as described in 'academic beneficiaries".
There is considerable interest from the pharmaceutical industry in discovering regulators of inflammation resolution, which are fundamental in a range of disease settings. In my own clinical speciality of respiratory medicine, Chronic Obstructive Pulmonary Disease is a major cause of morbidity and mortality which lacks effective treatments. Many examples exist in all clinical specialities. We anticipate that the unique nature of the mechanisms investigated in this Programme will make them attractive targets for anti-inflammatory therapeutics. Protection of IP for these targets as they are discovered will bring significant economic gains to UK plc. Integration with the Pharma industry will allow rapid drug development, building on existing collaborations such as the MICA collaboration with GlaxoSmithKline for Aim 2 of this proposal.
It is my ultimate aim that drugs identified in my research programme find their way into my clinical practice to treat patients who I currently cannot offer effective treatments. This programme will deliver successful identification of drug targets and identification of lead candidates which I hope will ultimately have an impact on patient care. The approaches I have developed are suitable for drug repurposing, and identification of compounds such as Tanshinone IIA (used in China to treat cardiovascular disease) shows how this might be possible. Experimental Medicine approaches are in development to take forward such advances towards clinical use. The project will validate approaches for the identification of new small molecular inhibitors of retention signalling in inflammation. This leads to obvious longer-term commercial opportunities to develop the technology to a higher throughput level, and to engage industrial partners in developing new therapies. Via existing and new links, we will encourage Pharma investment in this programme, and develop IP sharing arrangements to ensure mutual benefit from emerging knowledge and know how.
The advances in knowledge, and potential for driving drug development will ultimately impact on quality of life, health and well-being. Avoidance of dysregulated inflammation is a prerequisite for healthy ageing.
The project uses cross-disciplinary approaches from mammalian cell biology, zebrafish models and molecular biology. These methodologies will be used to develop and make use of innovative approaches to the study of inflammation in vivo. The project will contribute to new expertise in developing these unique tools to address biological questions by a systematic, and ultimately, high throughput approach. The project will strengthen links between different disciplines and forge a greater understanding of how we can engage, complement and enhance research for the future.
This proposal will deliver highly trained researchers offering unique skills. The PDRAs will combine skills in fish models and state of the art in vivo microscopy, in parallel with human primary cell-based assays. They will develop distinctive skills in generating new datasets and new approaches to understanding biological problems. This expertise will provide transferable skills to other non-academic beneficiaries, but will also be used to train researchers from other groups in our methodologies.
The PDRAs and myself are actively involved in public engagement and broader dissemination, with regular school visits and high-level involvement with public exhibitions such as Royal Society Summer Science exhibition, and the University of Sheffield Festival of the Mind.
There is considerable interest from the pharmaceutical industry in discovering regulators of inflammation resolution, which are fundamental in a range of disease settings. In my own clinical speciality of respiratory medicine, Chronic Obstructive Pulmonary Disease is a major cause of morbidity and mortality which lacks effective treatments. Many examples exist in all clinical specialities. We anticipate that the unique nature of the mechanisms investigated in this Programme will make them attractive targets for anti-inflammatory therapeutics. Protection of IP for these targets as they are discovered will bring significant economic gains to UK plc. Integration with the Pharma industry will allow rapid drug development, building on existing collaborations such as the MICA collaboration with GlaxoSmithKline for Aim 2 of this proposal.
It is my ultimate aim that drugs identified in my research programme find their way into my clinical practice to treat patients who I currently cannot offer effective treatments. This programme will deliver successful identification of drug targets and identification of lead candidates which I hope will ultimately have an impact on patient care. The approaches I have developed are suitable for drug repurposing, and identification of compounds such as Tanshinone IIA (used in China to treat cardiovascular disease) shows how this might be possible. Experimental Medicine approaches are in development to take forward such advances towards clinical use. The project will validate approaches for the identification of new small molecular inhibitors of retention signalling in inflammation. This leads to obvious longer-term commercial opportunities to develop the technology to a higher throughput level, and to engage industrial partners in developing new therapies. Via existing and new links, we will encourage Pharma investment in this programme, and develop IP sharing arrangements to ensure mutual benefit from emerging knowledge and know how.
The advances in knowledge, and potential for driving drug development will ultimately impact on quality of life, health and well-being. Avoidance of dysregulated inflammation is a prerequisite for healthy ageing.
The project uses cross-disciplinary approaches from mammalian cell biology, zebrafish models and molecular biology. These methodologies will be used to develop and make use of innovative approaches to the study of inflammation in vivo. The project will contribute to new expertise in developing these unique tools to address biological questions by a systematic, and ultimately, high throughput approach. The project will strengthen links between different disciplines and forge a greater understanding of how we can engage, complement and enhance research for the future.
This proposal will deliver highly trained researchers offering unique skills. The PDRAs will combine skills in fish models and state of the art in vivo microscopy, in parallel with human primary cell-based assays. They will develop distinctive skills in generating new datasets and new approaches to understanding biological problems. This expertise will provide transferable skills to other non-academic beneficiaries, but will also be used to train researchers from other groups in our methodologies.
The PDRAs and myself are actively involved in public engagement and broader dissemination, with regular school visits and high-level involvement with public exhibitions such as Royal Society Summer Science exhibition, and the University of Sheffield Festival of the Mind.
Organisations
- University of Sheffield (Lead Research Organisation)
- University College London (Collaboration)
- HARVARD UNIVERSITY (Collaboration)
- University of Manchester (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- French Institute of Health and Medical Research (Collaboration)
- University of Sheffield (Collaboration)
- University Medical Center Utrecht (UMC) (Collaboration)
- Versailles Saint-Quentin-en-Yvelines University (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Agency for Science, Technology and Research (A*STAR) (Collaboration)
- Wellcome Sanger Institute (Project Partner)
- GlaxoSmithKline (United Kingdom) (Project Partner)
- European Molecular Biology Laboratory (Project Partner)
- Harvard University (Project Partner)
- University of Birmingham (Project Partner)
- GlaxoSmithKline (United States) (Project Partner)
Publications
Batalha IL
(2019)
Polymeric nanobiotics as a novel treatment for mycobacterial infections.
in Journal of controlled release : official journal of the Controlled Release Society
Bernut A
(2019)
CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses.
in Cell reports
Bernut A
(2020)
Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation.
in Frontiers in immunology
Bojarczuk A
(2016)
Cryptococcus neoformans Intracellular Proliferation and Capsule Size Determines Early Macrophage Control of Infection.
in Scientific reports
Boldock E
(2018)
Human skin commensals augment Staphylococcus aureus pathogenesis.
in Nature microbiology
Buchan K
(2019)
A transgenic zebrafish line for in vivo visualisation of neutrophil myeloperoxidase
in PLOS ONE
Buchan KD
(2021)
Human-specific staphylococcal virulence factors enhance pathogenicity in a humanised zebrafish C5a receptor model.
in Journal of cell science
Buchan KD
(2019)
Staphylococcus aureus: setting its sights on the human innate immune system.
in Microbiology (Reading, England)
Connolly J
(2017)
Identification of Staphylococcus aureus Factors Required for Pathogenicity and Growth in Human Blood.
in Infection and immunity
Elks PM
(2015)
Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models.
in Disease models & mechanisms
Ellett F
(2015)
Defining the phenotype of neutrophils following reverse migration in zebrafish.
in Journal of leukocyte biology
Ellis PS
(2022)
A subset of gut leukocytes has telomerase-dependent "hyper-long" telomeres and require telomerase for function in zebrafish.
in Immunity & ageing : I & A
Foulkes M
(2017)
Expression and regulation of drug transporters in vertebrate neutrophils
in Scientific Reports
Foulkes MJ
(2020)
Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish.
in PloS one
Gibson JF
(2022)
Blood vessel occlusion by Cryptococcus neoformans is a mechanism for haemorrhagic dissemination of infection.
in PLoS pathogens
Hamilton N
(2018)
A method for transplantation of human HSCs into zebrafish, to replace humanised murine transplantation models.
in F1000Research
Hamilton N
(2018)
A method for transplantation of human HSCs into zebrafish, to replace humanised murine transplantation models
in F1000Research
Hepburn L
(2014)
Innate immunity. A Spaetzle-like role for nerve growth factor ß in vertebrate immunity to Staphylococcus aureus.
in Science (New York, N.Y.)
Herman KD
(2022)
The EGFR/ErbB inhibitor neratinib modifies the neutrophil phosphoproteome and promotes apoptosis and clearance by airway macrophages.
in Frontiers in immunology
Isles HM
(2021)
Pioneer neutrophils release chromatin within in vivo swarms.
in eLife
Isles HM
(2019)
The CXCL12/CXCR4 Signaling Axis Retains Neutrophils at Inflammatory Sites in Zebrafish.
in Frontiers in immunology
Kadochnikova A
(2018)
Estimation of Hidden Chemoattractant Field from Observed Cell Migration Patterns
in IFAC-PapersOnLine
Le Moigne V
(2022)
Roscovitine Worsens Mycobacterium abscessus Infection by Reducing DUOX2-mediated Neutrophil Response.
in American journal of respiratory cell and molecular biology
Lee JA
(2017)
Zebrafish screens for new colitis treatments - a bottom-up approach.
in The FEBS journal
Messad N
(2015)
Existence of a Colonizing Staphylococcus aureus Strain Isolated in Diabetic Foot Ulcers.
in Diabetes
Nourshargh S
(2016)
Reverse Migration of Neutrophils: Where, When, How, and Why?
in Trends in Immunology
Ogryzko N
(2014)
The IL-1 family in fish: Swimming through the muddy waters of inflammasome evolution
in Developmental & Comparative Immunology
Ogryzko NV
(2019)
Hif-1a-Induced Expression of Il-1ß Protects against Mycobacterial Infection in Zebrafish.
in Journal of immunology (Baltimore, Md. : 1950)
Plant T
(2020)
Semaphorin 3F signaling actively retains neutrophils at sites of inflammation.
in The Journal of clinical investigation
Prajsnar T
(2022)
Phagosomal Acidification Is Required to Kill Streptococcus pneumoniae in a Zebrafish Model
in Cellular Microbiology
Prajsnar TK
(2018)
Use of Larval Zebrafish Model to Study Within-Host Infection Dynamics.
in Methods in molecular biology (Clifton, N.J.)
Description | (INFLANET) - Training European Experts in Inflammation: from the molecular players to animal models and the bedside |
Amount | € 3,977,117 (EUR) |
Funding ID | 955576 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 03/2021 |
End | 02/2025 |
Description | BIA Fellowship to Robbie Evans |
Amount | £66,460 (GBP) |
Organisation | British Infection Association (BIA) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2015 |
End | 11/2016 |
Description | Developing an in vivo CRISPR-interference Screening Resource |
Amount | £428,223 (GBP) |
Funding ID | BB/R015457/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2018 |
End | 08/2021 |
Description | Discovery Medicine North DTP in Discovery Medicine across the Lifecourse |
Amount | £3,300,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2016 |
End | 01/2021 |
Description | ELA International Fellowship (NH) |
Amount | £240,000 (GBP) |
Organisation | European Leukodystrophy Association (ELA) |
Sector | Charity/Non Profit |
Country | European Union (EU) |
Start | 12/2016 |
End | 12/2019 |
Description | IMI |
Amount | € 24,000,000 (EUR) |
Organisation | European Commission |
Department | Innovative Medicines Initiative (IMI) |
Sector | Public |
Country | Belgium |
Start | 07/2017 |
End | 08/2022 |
Description | MICA: Mitochondrial dysfunction in macrophages and impaired bacterial clearance in chronic obstructive pulmonary disease (COPD) |
Amount | £1,586,149 (GBP) |
Funding ID | MR/W028506/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2022 |
End | 11/2027 |
Description | MRC Antimicrobial Resistance Networks |
Amount | £2,800,000 (GBP) |
Funding ID | MR/N02995X/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2016 |
End | 08/2021 |
Description | MRC CIMA studentships |
Amount | £120,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2018 |
End | 10/2022 |
Description | MRC Project Grant |
Amount | £691,917 (GBP) |
Funding ID | MR/R001111/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2018 |
End | 01/2021 |
Description | MRC Project Grant |
Amount | £412,769 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2019 |
End | 12/2022 |
Description | NC3Rs Pilot Grant |
Amount | £98,500 (GBP) |
Funding ID | NC/M001490/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 03/2015 |
End | 10/2016 |
Description | Strategic Research Centre |
Amount | £750,000 (GBP) |
Funding ID | SRC018 |
Organisation | Cystic Fibrosis Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2021 |
End | 12/2025 |
Description | Wellcome Trust Clinical Research Training Fellowship |
Amount | £249,928 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Research Training Fellowship |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2015 |
End | 09/2018 |
Description | Wellcome Trust Clinical Training Fellowship |
Amount | £250,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2018 |
End | 01/2021 |
Title | Lyz:Halo |
Description | Lyz:Halo tag transgenic zebrafish line |
Type Of Material | Model of mechanisms or symptoms - non-mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | No |
Impact | In progress |
Title | lyz:dCas9 |
Description | lyz:dCas9 transgenic zebrafish line |
Type Of Material | Model of mechanisms or symptoms - non-mammalian in vivo |
Year Produced | 2017 |
Provided To Others? | No |
Impact | In progress |
Title | mpeg:dCas9 |
Description | mpeg:dCAs9 transgenic zebrafish line |
Type Of Material | Model of mechanisms or symptoms - non-mammalian in vivo |
Year Produced | 2017 |
Provided To Others? | No |
Impact | In progress |
Description | Bridging zebrafish models of inflammation and Pharma drug screening |
Organisation | GlaxoSmithKline (GSK) |
Department | Experimental Medicine Unit |
Country | United Kingdom |
Sector | Private |
PI Contribution | New targets identified in academic setting and in vivo drug screening approaches. |
Collaborator Contribution | Expertise in drug development and DMPK, expertise in Experimental medicine and drug discovery. |
Impact | MRC Industry Partnership Award. Agreement to collaborate as MICA partner on Programme Grant application. Manuscript in preparation. |
Start Year | 2012 |
Description | Future Transplantation Techniques - Zon |
Organisation | Harvard University |
Department | Department of Stem Cell and Regenerative Biology |
Country | United States |
Sector | Academic/University |
PI Contribution | We provided images showing human cells could transplant the same way as zebrafish cells in the developing zebrafish host, thus confirming previous data obtained by Zon's team. |
Collaborator Contribution | Provided us with technical help when developing the technique. |
Impact | None yet. |
Start Year | 2016 |
Description | Il-1 processing and release |
Organisation | University of Sheffield |
Department | Department of Cardiovascular Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided ZF knowledge and expertise to a mammalian cell biology project to allow in vivo study. |
Collaborator Contribution | Colllaborative effort to study Il-1b processing, release and targetting in vivo. |
Impact | A number of transgenic reagents have been generated, or are in the process of being generated. Manuscripts and grant applications are planned in the new year. Transgenic reagents produced: UAS:Il-1.GFP line UAS:Il-1.mCherry Mpeg1:il-1.GFP line BBSRC project grant BHF project grant Manuscript in Disease Models and Mechanisms. |
Start Year | 2008 |
Description | Il-34 in zebrafish |
Organisation | University of Sheffield |
Department | Department of Oncology and Metabolism |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in zebrafish mutagenesis and imaging, inflammation |
Collaborator Contribution | Expertise in IL-34 biology |
Impact | PhD student working on generating and characterising fish mutants |
Start Year | 2015 |
Description | Infection in cystic fibrosis models Laurent Kremer |
Organisation | French Institute of Health and Medical Research |
Country | France |
Sector | Public |
PI Contribution | Provided expertise in zebrafish innate immunity and modelling of infection in zebrafish, clinical insights into CF. |
Collaborator Contribution | Expertise in mycobacterial infection. |
Impact | https://doi.org/10.1016/j.celrep.2019.01.071 Marie Sklowdowska-Curie Intraeuropean Fellowship to Audrey Bernut. |
Start Year | 2016 |
Description | Inflammation in ATM mutants |
Organisation | University of Sheffield |
Department | Department of Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Inflammation expertise |
Collaborator Contribution | Neuroscience expertise |
Impact | In progress |
Start Year | 2017 |
Description | Inflammation in cystic fibrosis models |
Organisation | Versailles Saint-Quentin-en-Yvelines University |
Country | France |
Sector | Academic/University |
PI Contribution | Previous Fellow Audrey Bernut has moved here and we continue to collaborate. I have provided inflammation support to this programme of work. |
Collaborator Contribution | Scientific knowledge and approaches. |
Impact | Several manuscripts and further grant funding. |
Start Year | 2020 |
Description | Jim Wild |
Organisation | University of Sheffield |
Department | Faculty of Medicine, Dentistry and Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided clinical input to collaborative project and clinical academic guidance to supervised clinician scientist. |
Collaborator Contribution | Provided MRI physics and imaging expertise to partnership. |
Impact | PMID: 30389827 Grant funding from IMI programme of Horizon 2020 |
Start Year | 2015 |
Description | Larger blood volume for transplant studies - Snowden |
Organisation | University of Sheffield |
Department | School of Clinical Dentistry Sheffield |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | NA |
Collaborator Contribution | Offered to include our study in his ethics to allow access to larger volume of human blood to perform larger experiments |
Impact | None yet. |
Start Year | 2016 |
Description | MRI imaging as a biomarker for Interstitial Lung Disease |
Organisation | University of Sheffield |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in ILD, academic clinical mentoring of Fellow |
Collaborator Contribution | Expertise in MRI imaging |
Impact | IMI TRISTAN.Multi-disciplinary. Physics, medicine |
Start Year | 2015 |
Description | Macrophage project. |
Organisation | University of Sheffield |
Department | MRC Centre for Developmental and Biomedical Genetics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided expertise in generation of transgenic zebrafish, and in the study of immune cell biology in vivo. |
Collaborator Contribution | Developed tools collaboratively for the study of macrophages in vivo. |
Impact | PMID: 21225092 Recruited Felix Ellett from Australia on AHMRC CJ Martin fellowship to work on this project. |
Start Year | 2008 |
Description | Microglia and GBA deficiency |
Organisation | University of Sheffield |
Department | Department of Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provision of expertise and transgenic lines for the study of microglia. |
Collaborator Contribution | Mutant zebrafish and characterisation of mutants. |
Impact | Manuscript in Human Molecular Genetics. |
Start Year | 2015 |
Description | Neurotrophins and infection |
Organisation | University of Cambridge |
Department | Cambridge Institute for Medical Research (CIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise and experimentation in zebrafish models of Staph infection. |
Collaborator Contribution | Expertise in in vitro cell biology of infection. |
Impact | Manuscript published in Science. |
Start Year | 2011 |
Description | Neutrophil Kinome - Lynne Prince |
Organisation | University of Sheffield |
Department | Faculty of Medicine, Dentistry and Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Biology of zebrafish neutrophils, screen of compounds against zebrafish neutrophilic inflammation. Characterisation of the neutrophil kinome. |
Collaborator Contribution | Biology of human neutrophils, screen of compounds against human neutrophil apoptosis. |
Impact | Manuscript in revision. |
Start Year | 2016 |
Description | Neutrophil viscosity in vivo |
Organisation | University of Cambridge |
Department | Cambridge Institute for Medical Research (CIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Developed transgenic reagent for measuring neutrophil viscosity in vivo |
Collaborator Contribution | Provided essential scientific input and guidance |
Impact | In progress |
Start Year | 2016 |
Description | PI3K in fish |
Organisation | University of Sheffield |
Department | Department of Infection, Immunity and Cardiovascular Disease |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in Zebrafish as a model of immunity |
Collaborator Contribution | PI3K biology |
Impact | Wellcome Clinical Research Training Fellowship. BHF grant to my collaborator. |
Start Year | 2015 |
Description | Paediatric leukodystrophies |
Organisation | University of Sheffield |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Supported Noémie Hamilton as she establishes her research programme. The work in this grant directly supported Noemie's transition to her own PDRA fellowship. |
Collaborator Contribution | Noémie has developed models of childhood leukodystrophies. |
Impact | Manuscript in resubmission for Glia. Several unsuccessful grant applications, further applications in preparation. |
Start Year | 2016 |
Description | Polymersomes for neutrophil manipulation |
Organisation | University College London |
Department | Department of Chemistry |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in neutrophil biology, co-supervised student. |
Collaborator Contribution | Expertise on polymer some biology, co-supervised student. |
Impact | MRC CDBG Studentship PMID: 23033321 Other manuscripts in preparation. |
Start Year | 2009 |
Description | Polymersomes for neutrophil manipulation |
Organisation | University of Sheffield |
Department | Department of Biomedical Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in neutrophil biology, co-supervised student. |
Collaborator Contribution | Expertise on polymer some biology, co-supervised student. |
Impact | MRC CDBG Studentship PMID: 23033321 Other manuscripts in preparation. |
Start Year | 2009 |
Description | SGK1 biology in zebrafish |
Organisation | University of Manchester |
Department | Faculty of Life Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in inflammation biology and apoptosis siganlling in neutrophils. |
Collaborator Contribution | Expertise on SGK1 biology in zebrafish |
Impact | Manuscript published in Journal of Immunology. |
Start Year | 2011 |
Description | Semaforin 3F as a neutrophil retention signal |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Generated zebrafish model of semaforin 3f deficiency, identified role of sema3f in neutrophil function. |
Collaborator Contribution | Initiated study and continued work in human and mouse tissues. |
Impact | Manuscript in Journal of Clinical Investigation, multidisciplinary. |
Start Year | 2012 |
Description | Singapore inflammation project |
Organisation | Agency for Science, Technology and Research (A*STAR) |
Department | Institute of Molecular and Cell Biology, |
Country | Singapore |
Sector | Academic/University |
PI Contribution | Expertise, shared experimental design and manscuript preparation. |
Collaborator Contribution | generation of shared reagents, sharing expertise |
Impact | New technology generated, tools shared. PMID: 21555741 Drug screen manuscript published in Disease Models and Mechanisms PMID: 24291762 |
Start Year | 2008 |
Description | Staphylococcus aureus host-specificity - JAG van Strijp |
Organisation | University Medical Center Utrecht (UMC) |
Department | De Hoogstraat Rehabilitation Centre |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | Provided zebrafish expertise to collaborative endeavour to generate transgenic zebrafish expressing humanised targets for staph aureus toxins. |
Collaborator Contribution | Provided expertise on staphyloccal toxins. |
Impact | PMID: 30625113 PMID: 30013237 Other manuscripts in revision. |
Start Year | 2014 |
Description | Stefan Marciniak |
Organisation | University of Cambridge |
Department | Cambridge Institute for Medical Research (CIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Idea that zebrafish might be an ideal system to test whether neutrophil viscosity might alter in vivo. |
Collaborator Contribution | Bodipy rotor, HaloTag combination to read out viscosity in vivo. |
Impact | Awaited. |
Start Year | 2016 |
Description | The neutrophil kinome |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | Provision of in vivo models and assays. Hypothesis to be tested. |
Collaborator Contribution | Kinase pharmacology expertise, compounds, analysis. |
Impact | MICA component to Programme grant funding. |
Start Year | 2014 |
Description | Zebrafish models of Senescence |
Organisation | University of Sheffield |
Department | Department of Oncology and Metabolism |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in zebrafish transgensis, inflammation and imaging. |
Collaborator Contribution | Expertise in senescence |
Impact | PhD student, funded by BBSRC |
Start Year | 2015 |
Description | Discovery Night (Sheffield) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Earn your zebrafish stripes - Members of the public were invited to earn their stripes by creating visual delights and going on a zebrafish tour of the world. The Bateson Centre Zebrafish Facility has the capacity to hold over 112,000 fish and is one of the largest facilities in the UK. Visitors found out why we keep so many tropical freshwater fish and explored the relevance of zebrafish in medical research at an interactive exhibition. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.sheffield.ac.uk/discoverynight/index |
Description | Invited Seminar speaker, Kennedy Institute, Oxford |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Invited Seminar Speaker, Kennedy Institute of Rheumatology, Oxford. |
Year(s) Of Engagement Activity | 2019 |
Description | Invited Seminar speaker, Kings College London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Invited seminar speaker at the Centre for Craniofacial and Regenerative Biology, Kings College London. |
Year(s) Of Engagement Activity | 2019 |
Description | Invited speaker - Max Planck Institute for Infection Biology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Invited speaker to the Max Planck Institute for Infection Biology 'Neutrophil migration patterns in regulating inflammation'. Berlin, Germany, January 2019. |
Year(s) Of Engagement Activity | 2019 |
Description | Krebs Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Demonstrated how scientists at the Bateson Centre work with zebrafish to study a range of diseases. Used microscopes to observe the transparent embryos, and see the heart pumping and blood circulating. |
Year(s) Of Engagement Activity | 2015 |
URL | http://krebsfest.group.shef.ac.uk/programme/public-night/ |
Description | Life: A Festival of Health, from Head to Toe, Our Microscopic Army Against Disease (Sheffield) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Members of the public were shown how we use flies, fish and amoebae to understand the biology of white blood cells during disease. Activities included: fluorescence microscopy of the live organisms, 3D-fluorescent printed models of each organism, informative posters, timelapse microscopy videos and handouts. |
Year(s) Of Engagement Activity | 2016 |
URL | http://microarmy.weebly.com/ |
Description | Life: A Festival of Medicine, Dentistry and Health |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | We presented an exhibition, demonstrating how zebrafish can help us understand human disease. Members of the public took part in a range of activities, including looking at live transgenic zebrafish through the microscope. |
Year(s) Of Engagement Activity | 2014 |
Description | Symposium presentation at American Thoracic Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Symposium presentation at American Thoracic Society, Denver, May 20th 2015. Invited Speaker. New insights into neutrophilic pulmonary inflammation. |
Year(s) Of Engagement Activity | 2015 |
Description | ZDM8 Boston MA. September 2015 Invited Speaker. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | ZDM8 Boston MA. September 2015 Invited Speaker. |
Year(s) Of Engagement Activity | 2015 |