Premature death and organ hypofunction after severe acute pancreatitis results from cellular senescence - mechanisms and new opportunities for therapy
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Inflammation Research
Abstract
We have discovered that after a serious illness, for example one that needs treatment in intensive care, some people's vital organs do not work as well as they should. This negative effect can last for months and sometimes years afterwards. We have also discovered that people who have suffered a serious illness have a shorter life expectancy compared to others of a similar age, gender and overall general health. This happens even though these individuals appear to have made a complete recovery from their original illness. We believe that this is a serious problem for them and for society as a whole. Our goal is to help people to recover to their full potential after suffering a life-threatening illness.
The idea behind our science is that serious illness results in premature ageing of vital organs within the body, for example the heart and lungs. Our idea is based on discoveries made over many years by us and other scientists. Whenever a cell divides in order for a person to grow or a vital organ to repair itself, for example the cells lining the bowel, liver cells and white blood cells of the immune system, that cell gets a little bit older. After a cell has divided a number of times, or if the DNA inside the cell gets damaged beyond repair, for example during a serious illness, that cell becomes aged. It is likely that these aged cells have stopped working properly. We think that inflammation during a serious illness leads to quicker and earlier aging of cells and that reduces a person's life expectancy.
My area of expertise is looking after patients whose cells have become damaged during a serious illness called acute pancreatitis. Acute pancreatitis is inflammation in the pancreas - a vital organ that controls the digestion of food and blood sugar levels. Our research will be very helpful to people who have had pancreatitis and to those people who look after them. Added to that, we also think that our discoveries will be useful to other scientists and health professionals who study other serious illness, for example severe trauma or major surgery.
Our research will use modern scientific techniques in the laboratory and build on what is already known in the scientific community. We are also going to invite patients who are recovering from pancreatitis to donate blood samples in order to measure damage in their cells, and do some medical tests over a period of time to see how their organs have aged as a result of pancreatitis, and to see how well they recover. When we have a better understanding of how cell damage and cell ageing are linked, we will be able to plan ways to improve a person's recovery after serious illness. We will share our discoveries with the scientific community, and work together to reach our goals.
The idea behind our science is that serious illness results in premature ageing of vital organs within the body, for example the heart and lungs. Our idea is based on discoveries made over many years by us and other scientists. Whenever a cell divides in order for a person to grow or a vital organ to repair itself, for example the cells lining the bowel, liver cells and white blood cells of the immune system, that cell gets a little bit older. After a cell has divided a number of times, or if the DNA inside the cell gets damaged beyond repair, for example during a serious illness, that cell becomes aged. It is likely that these aged cells have stopped working properly. We think that inflammation during a serious illness leads to quicker and earlier aging of cells and that reduces a person's life expectancy.
My area of expertise is looking after patients whose cells have become damaged during a serious illness called acute pancreatitis. Acute pancreatitis is inflammation in the pancreas - a vital organ that controls the digestion of food and blood sugar levels. Our research will be very helpful to people who have had pancreatitis and to those people who look after them. Added to that, we also think that our discoveries will be useful to other scientists and health professionals who study other serious illness, for example severe trauma or major surgery.
Our research will use modern scientific techniques in the laboratory and build on what is already known in the scientific community. We are also going to invite patients who are recovering from pancreatitis to donate blood samples in order to measure damage in their cells, and do some medical tests over a period of time to see how their organs have aged as a result of pancreatitis, and to see how well they recover. When we have a better understanding of how cell damage and cell ageing are linked, we will be able to plan ways to improve a person's recovery after serious illness. We will share our discoveries with the scientific community, and work together to reach our goals.
Technical Summary
Even after an apparently complete clinical recovery from an episode of critical illness - for which severe acute pancreatitis (AP) is a paradigm - life expectancy is reduced. In this fellowship, I will investigate the molecular mechanisms that underpin that deleterious legacy, with particular focus on increased flux through kynurenine monooxygenase (KMO) as a key contributor to sterile systemic inflammation and post-inflammatory senescence.
I will define precisely the mechanistic contribution of the kynurenine pathway of tryptophan metabolism, and specifically KMO, on whole-organism and organ-specific accelerated senescence following sterile systemic inflammation using the paradigm model of acute pancreatitis (AP) in human patients and experimental animal models. This coherent portfolio of experiments will dissect the mechanisms by which increased kynurenine pathway flux initiates the DNA damage response (DDR), focusing on oxidative stress generated by the KMO product 3-hydroxykynurenine (3HK), and examining closely the role of the telomere deprotection response (TDR), using models in yeast, primary human lung fibroblasts in vitro, and experimental mouse and rat models of AP. With collaborators, I will develop and validate a novel PET tracer in order to define the organ-specific KMO activity profile during experimental AP and allow correlation with organ-specific post-inflammatory senescence at subsequent time points. Biological indices of the DDR, TDR, the senescence-associated secretory phenotype, cellular and whole-organism senescence will be examined in models and contextualized to chronic organ hypofunction in a clinical cohort as a legacy of human AP and AP-MODS.
I will define precisely the mechanistic contribution of the kynurenine pathway of tryptophan metabolism, and specifically KMO, on whole-organism and organ-specific accelerated senescence following sterile systemic inflammation using the paradigm model of acute pancreatitis (AP) in human patients and experimental animal models. This coherent portfolio of experiments will dissect the mechanisms by which increased kynurenine pathway flux initiates the DNA damage response (DDR), focusing on oxidative stress generated by the KMO product 3-hydroxykynurenine (3HK), and examining closely the role of the telomere deprotection response (TDR), using models in yeast, primary human lung fibroblasts in vitro, and experimental mouse and rat models of AP. With collaborators, I will develop and validate a novel PET tracer in order to define the organ-specific KMO activity profile during experimental AP and allow correlation with organ-specific post-inflammatory senescence at subsequent time points. Biological indices of the DDR, TDR, the senescence-associated secretory phenotype, cellular and whole-organism senescence will be examined in models and contextualized to chronic organ hypofunction in a clinical cohort as a legacy of human AP and AP-MODS.
Planned Impact
This project deals with the effect of severe whole-body inflammation on premature cellular ageing, and how individuals recover after critical illness to a state that allows them to return to a healthy and productive life. Therefore, this research is of importance to multiple sections of society, including individuals who have suffered an episode of critical illness, families and loved ones, local communities, healthcare organizations, policy makers and healthcare providers. We will strive for excellence with impact, and maximize the economic and societal benefits of this research. By understanding the deleterious legacy of critical illness, over time we will be able to improve recovery and prevent lasting organ damage. We envisage that this will increase the likelihood of individuals at working age returning to their chosen work, with the economic benefits that that will bring, individually and to society, decrease the burden on health resources and increase happiness through increased physical and mental well being. In an ageing population, understanding the molecular processes that contribute to the ageing process, especially after an episode of critical illness will undoubtedly increase in importance. I am focusing on acute pancreatitis (AP), which affects 30,000 individuals in the UK every year, but we expect that the underlying molecular mechanisms that we will define will be translatable to other situations of systemic inflammation, for example trauma and major surgery. Because of the overlap between the DNA damage response, ageing and cancer, there is a high likelihood that our work will also shed light on how cancer can develop after long-standing inflammation. Importantly, in the execution of our project, we will be mindful of the different potential pathways of realizing impacts, such that the funding invested in the project by the MRC is used to its maximum potential. Life sciences research is integral to society and the UK economy, and the UK has always punched above its weight in this sector. Having maximum impact and using that economic potential to the full is one of our uppermost priorities. It is through these vehicles that we can use our research skills, our communication and networking skills to encourage inward investment to UK Life Sciences research and boost the economy. The short-term economic benefits of our research are important, in terms of encouraging inward investment to the UK and collaborating with important players in UK plc., for example our interdisciplinary DPAc with GSK. In the longer term, we will maximize knowledge exchange and translation to generate the widest range of economic and societal benefits through this internationally competitive research project. This research project has the potential to give significant insight into the healing process and preventing lasting organ damage; this knowledge will enable innovations that speed-up recovery and guide individuals back to a better state of health after critical illness. Translation of these interventions may be complex - developing new medicines (for which we have experience); of medium complexity - repurposing existing medicines; or straightforward in concept (if not necessarily execution) - for example dietary or lifestyle interventions, or increased awareness of problems that individuals might expect to experience. I am fortunate to be in regular contact with Third Sector organizations, in particular Core (a charity that funds research, public engagement, patient information, focusing on gastrointestinal disease and pancreatitis) and The Health Foundation, an influential independent charity that engages in policy and healthcare development in strategic ways. I will use those networks, and all my other networks, especially my peer group and professional community to maximize our impact. I hope to join with others in our shared commitment to promote a dynamic and internationally competitive research and innovation base in the UK.
Organisations
- University of Edinburgh (Fellow, Lead Research Organisation)
- University of Manchester (Collaboration)
- Rockefeller University (Collaboration)
- IBM (Collaboration)
- NHS Greater Glasgow and Clyde (NHSGGC) (Collaboration)
- Newcastle University (Collaboration)
- Salk Institute for Biological Studies (Collaboration)
- University of Warwick (Collaboration)
- Information Services Division (ISD) (Collaboration)
- University of Dundee (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- Perspectum (Collaboration)
- Cardiff University (Collaboration)
- UNIVERSITY OF GLASGOW (Collaboration)
- Heriot-Watt University (Collaboration)
- UNIVERSITY OF BIRMINGHAM (Collaboration)
- STRATIFIED MEDICINE SCOTLAND INNOVATION CENTRE (Collaboration)
- Eagle Genomics Ltd (Collaboration)
- Critical Path Institute (Collaboration)
- ScottisH Informatics Programme (SHIP) (Collaboration)
- UNIVERSITY OF LIVERPOOL (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- University of Bristol (Collaboration)
- UNIVERSITY OF SOUTHAMPTON (Collaboration)
Publications
Baillie JK
(2018)
Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.
in PLoS computational biology
Crittenden S
(2021)
Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells.
in Science advances
Cumpstey AF
(2020)
Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude - A randomised controlled trial (Xtreme Alps).
in Nitric oxide : biology and chemistry
Cumpstey AF
(2017)
Effects of dietary nitrate on respiratory physiology at high altitude - Results from the Xtreme Alps study.
in Nitric oxide : biology and chemistry
Di Martino M
(2023)
Timing of Cholecystectomy After Moderate and Severe Acute Biliary Pancreatitis.
in JAMA surgery
Dobie R
(2019)
Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis.
in Cell reports
Hayes A
(2017)
Benign liver lesions
in Surgery (Oxford)
Hayes AJ
(2023)
Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.
in Cell reports
Description | Contribution to Academy of Medical Sciences Value Setting Priorities |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Invitation to contribute: test out the values in a number of scenarios and agree how we implement these values in practice and how we communicate these values externally. To inform our discussion with wider perspectives, we are looking for external 'peer review' of how the Academy currently practices these values and input into how we might do this in the future. |
Description | Informing new Academy of Medical Sciences programme on industry-academe-NHS mobility |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Contribution to a committee to help inform new AMS programme on industry-academe-NHS mobility |
Description | Wellcome Health Exchange - Healthy Ageing - is the UK approaching healthy ageing research in the right way? |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
Description | Amelie Waring Fellowship - AJH |
Amount | £180,000 (GBP) |
Organisation | CORE Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2014 |
End | 07/2017 |
Description | Amelie Waring Fellowship - to James O'Kelly |
Amount | £179,422 (GBP) |
Organisation | CORE Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2019 |
End | 07/2022 |
Description | Defining the mechanistic role of kynurenine 3-monooxygenase in breast cancer |
Amount | £229,967 (GBP) |
Funding ID | 2018NovPR1203 |
Organisation | Breast Cancer Now |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2019 |
End | 07/2022 |
Description | Discovery Partnerships with Academia |
Amount | £3,200,000 (GBP) |
Organisation | GlaxoSmithKline (GSK) |
Department | Academic Discovery Performance Unit |
Sector | Private |
Country | Global |
Start | 10/2011 |
Description | Does impaired adipose tissue B cell function lead to loss of natural antibody secretion and increase susceptibility to infection in obesity? |
Amount | £550,000 (GBP) |
Funding ID | 10873847 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2022 |
End | 12/2024 |
Description | Equity Investment in Kynos Therapeutics Ltd |
Amount | £1,500,000 (GBP) |
Organisation | Scottish Enterprise |
Sector | Public |
Country | United Kingdom |
Start | 02/2022 |
Description | Equity Investment in Kynos Therapeutics Ltd |
Amount | £2,500,000 (GBP) |
Organisation | IP Group Plc |
Sector | Private |
Country | United Kingdom |
Start | 02/2022 |
Description | Equity investment in Kynos Therapeutics Ltd |
Amount | £2,500,000 (GBP) |
Organisation | Epidarex |
Sector | Private |
Country | United Kingdom |
Start | 02/2022 |
Description | Kynurenine-3-monooxygenase inhibition as a novel therapeutic strategy to enhance islet cell viability and improve outcomes of Islet Transplantation |
Amount | £320,000 (GBP) |
Funding ID | 10485026 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2021 |
End | 11/2025 |
Description | MRC Confidence in Concept |
Amount | £1,200,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2019 |
End | 10/2019 |
Description | MRC Confidence in Concept |
Amount | £750,000 (GBP) |
Funding ID | MRC/CIC8/73 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2021 |
End | 02/2022 |
Description | MRC Doctoral Training Programme in Precision Medicine |
Amount | £5,000,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 02/2023 |
Description | MRC Stratified Medicines Initiative - Consortium Building Award |
Amount | £15,000 (GBP) |
Funding ID | MR/P027652/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2017 |
End | 11/2017 |
Description | Melville Trust PhD Studentship |
Amount | £83,667 (GBP) |
Organisation | Melville Trust for Care and Cure of Cancer |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2019 |
End | 04/2022 |
Description | Phase 1 Trial of KNS366 in Healthy Volunteers |
Amount | £2,560,000 (GBP) |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 04/2022 |
End | 09/2023 |
Description | Wellcome Trust Institutional Strategic Support Fund |
Amount | £80,000 (GBP) |
Funding ID | IS3-T03/02 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2017 |
End | 11/2017 |
Description | 3D bioprinting of pancreas cancer |
Organisation | Heriot-Watt University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Pancreas expertise; tissues samples |
Collaborator Contribution | 3D bioprinting; project leads |
Impact | Pending |
Start Year | 2018 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | Critical Path Institute |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | Eagle Genomics Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | NHS Greater Glasgow and Clyde (NHSGGC) |
Country | United Kingdom |
Sector | Public |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | Stratified Medicine Scotland Innovation Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Birmingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Dundee |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Edinburgh |
Department | The Roslin Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Liverpool |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Southampton |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | APPreSci - Acute Pancreatitis Precision Science |
Organisation | University of Warwick |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | CI and lead applicant to MRC Stratified Medicines Disease-focused call. Finalist. Outcome pending 2018 |
Collaborator Contribution | Consortium partners. |
Impact | MRC Stratified Medicine Initiative Consortium Building Award. |
Start Year | 2016 |
Description | Cell Crisis in Aging and Cancer Initiation |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Local organiser for international consensus meeting |
Collaborator Contribution | Lead and co-organiser |
Impact | International consensus meeting (virtual in 2022; in person 2023) |
Start Year | 2019 |
Description | Cell Crisis in Aging and Cancer Initiation |
Organisation | Rockefeller University |
Country | United States |
Sector | Academic/University |
PI Contribution | Local organiser for international consensus meeting |
Collaborator Contribution | Lead and co-organiser |
Impact | International consensus meeting (virtual in 2022; in person 2023) |
Start Year | 2019 |
Description | Cell Crisis in Aging and Cancer Initiation |
Organisation | Salk Institute for Biological Studies |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Local organiser for international consensus meeting |
Collaborator Contribution | Lead and co-organiser |
Impact | International consensus meeting (virtual in 2022; in person 2023) |
Start Year | 2019 |
Description | Circulating cell-free DNA as a biomarker for colorectal liver metastasis |
Organisation | University of Edinburgh |
Department | Institute of Genetics & Molecular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Conceptual formulation and sharing of biobank resources |
Collaborator Contribution | Conceptual formulation and sharing of biobank resources |
Impact | Pending |
Start Year | 2017 |
Description | Common factors driving chronic inflammatory disease and comorbidities |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are contributing expertise and know-how of the kynurenine pathway in inflammation, in particular regarding kynurenine monooxygenase (KMO); assays and tools e.g. genetically-altered mouse strains |
Collaborator Contribution | Expertise and know-how of the kynurenine pathway, particularly indoleamine deoxygenase (IDO); grant leadership; mechanistic experiments. |
Impact | Programme grant submission |
Start Year | 2017 |
Description | Development and validation of a KMO PET radio tracer |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | Radiochemistry; in vitro and in vivo assays |
Collaborator Contribution | Compound scaffold; radiochemistry expertise |
Impact | pending |
Start Year | 2017 |
Description | Fat-associated lymphoid tissue in inflammation |
Organisation | University of Edinburgh |
Department | Centre for Cardiovascular Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Coordinate surgical sampling through Edinburgh Surgery Translational Support Service |
Collaborator Contribution | Sample and Data Analysis |
Impact | MRC Project grant to Dr Cecile Benezech |
Start Year | 2019 |
Description | GSK DPAc |
Organisation | GlaxoSmithKline (GSK) |
Department | Academic Discovery Performance Unit |
Country | Global |
Sector | Private |
PI Contribution | We are enjoying a fruitful translational drug discovery partnership with GSK through the DPAc scheme to develop new therapies for multiple organ failure triggered by acute pancreatitis. We lead on the in vivo biology, disease expertise, clinical/translational relevance and cell based assays. |
Collaborator Contribution | GSK lead on high-throughput screening, medicinal chemistry, drug development, DMPK, formulation, safety and eventual product profile |
Impact | Academic papers, patents and other contractually sensitive output. |
Start Year | 2011 |
Description | HepaT1ca: Quantifying liver health in surgical candidates for liver malignancies |
Organisation | Perspectum |
Country | United Kingdom |
Sector | Private |
PI Contribution | Clinical Prinipal Investigator; protocol author; data capture; tissue sampling |
Collaborator Contribution | Signal processing; machine learning; productisation; |
Impact | InnovateUK funding |
Start Year | 2016 |
Description | ISLAND - Inflammation and Secondary Lymphoid Tissue in Health And Disease |
Organisation | University of Edinburgh |
Department | Centre for Cardiovascular Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Design and regulatory submission for approvals (HRA/NHS/REC) and coordination of human tissue donation as part of Edinburgh Surgery Translational Support Service |
Collaborator Contribution | Downstream utilisation of tissues in translational research |
Impact | Pending |
Start Year | 2022 |
Description | ISLAND - Inflammation and Secondary Lymphoid Tissue in Health And Disease |
Organisation | University of Edinburgh |
Department | School of Biological Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Design and regulatory submission for approvals (HRA/NHS/REC) and coordination of human tissue donation as part of Edinburgh Surgery Translational Support Service |
Collaborator Contribution | Downstream utilisation of tissues in translational research |
Impact | Pending |
Start Year | 2022 |
Description | KMO in breast cancer |
Organisation | University of Edinburgh |
Department | Institute of Genetics & Molecular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Preclinical and translational clinical evaluation of the role of KMO in breast cancer |
Collaborator Contribution | Preclinical and translational clinical evaluation of the role of KMO in breast cancer |
Impact | Pending |
Start Year | 2018 |
Description | Kynurenine biology in autoimmune disease |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Multiplex mass spectrometry analysis of kynurenine metabolites |
Collaborator Contribution | Evaluation of novel DNA sensing mechanisms in autoimmune diease |
Impact | Pending |
Start Year | 2018 |
Description | Methylomics in liquid biopsy for pancreas cancer |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Pancreas expertise; tissue access |
Collaborator Contribution | Sequencing; assay development; project leadership |
Impact | CRUK grant; Scottish Enterprise investment to PI |
Start Year | 2017 |
Description | SHIP study - pancreatitis |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | I lead on the clinical aspects of acute pancreatitis and translational implications of the epidemiology findings |
Collaborator Contribution | GSK - epidemiology and statistical expertise ISD - multi-source data collection, archiving, security, project management University of Dundee - study design, epidemiology, statistical expertise |
Impact | Pending |
Start Year | 2012 |
Description | SHIP study - pancreatitis |
Organisation | Information Services Division (ISD) |
Country | United Kingdom |
Sector | Public |
PI Contribution | I lead on the clinical aspects of acute pancreatitis and translational implications of the epidemiology findings |
Collaborator Contribution | GSK - epidemiology and statistical expertise ISD - multi-source data collection, archiving, security, project management University of Dundee - study design, epidemiology, statistical expertise |
Impact | Pending |
Start Year | 2012 |
Description | SHIP study - pancreatitis |
Organisation | ScottisH Informatics Programme (SHIP) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I lead on the clinical aspects of acute pancreatitis and translational implications of the epidemiology findings |
Collaborator Contribution | GSK - epidemiology and statistical expertise ISD - multi-source data collection, archiving, security, project management University of Dundee - study design, epidemiology, statistical expertise |
Impact | Pending |
Start Year | 2012 |
Description | SHIP study - pancreatitis |
Organisation | University of Dundee |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I lead on the clinical aspects of acute pancreatitis and translational implications of the epidemiology findings |
Collaborator Contribution | GSK - epidemiology and statistical expertise ISD - multi-source data collection, archiving, security, project management University of Dundee - study design, epidemiology, statistical expertise |
Impact | Pending |
Start Year | 2012 |
Description | Single cell RNA analysis in pancreas cancer early diagnosis |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Tissue and sample provision; pancreas cancer expertise |
Collaborator Contribution | Single cell RNA expertise; project leadership |
Impact | pending |
Start Year | 2017 |
Description | Telomere dysfunction in post-inflammatory settings |
Organisation | Salk Institute for Biological Studies |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | visiting research to Salk to study the role of KMO in telomere dysfunction during inflammation |
Collaborator Contribution | Expertise in telomere biology. Facilities. Mentoring. |
Impact | pending |
Start Year | 2017 |
Description | The role of autophagy in pancreatic cancer and pancreatitis |
Organisation | University of Edinburgh |
Department | Institute of Genetics and Cancer |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Pancreatitis expertise and human pancreas tissue ethically approved fixed tissue sections |
Collaborator Contribution | Mechanistic investigations into the role of autophagy in pancreatic cancer and pancreatitis |
Impact | Pending |
Start Year | 2022 |
Description | Therapeutic KMO Blockade to Prevent Cardiac Surgery-Associated Acute Kidney Injury |
Organisation | University of Bristol |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are leading this collaboration with UoB Translational Biomedical Research Centre |
Collaborator Contribution | Cardiac Surgery expertise and large animal model expertise |
Impact | pending |
Start Year | 2021 |
Description | Wellcome Trust Institutional Translational Partnership Award (Innovation Accelerator) Yunjie Yang |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Surgical translational expertise |
Collaborator Contribution | Advanced soft robotics for surgical robots |
Impact | Wellcome Trust Institutional Translational Partnership Award (Innovation Accelerator) Yunjie Yang |
Start Year | 2021 |
Description | Working group UoE IBM Watson potential partnership |
Organisation | IBM |
Country | United States |
Sector | Private |
PI Contribution | Working group discussions convened by Graham Spittle and Dave Robertston to engage with IBM Watson team |
Collaborator Contribution | Working group discussion |
Impact | Pending |
Start Year | 2019 |
Title | 3-(5-CHLORO-2-OXOBENZO[D]OXAZOL-3(2H)-YL)PROPANOIC ACID DERIVATIVES AS KMO INHIBITORS |
Description | A compound of formula (I) or a salt thereof are provided wherein R1, X and R3 are defined in the specification, useful in the treatment of disorders mediated by KMO such as acute pancreatitis, chronic kidney disease, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure. |
IP Reference | WO2015091647 |
Protection | Patent granted |
Year Protection Granted | 2015 |
Licensed | Commercial In Confidence |
Impact | Licensing/spin-out in progress |
Title | 3-(6-ALKOXY-5-CHLOROBENZO[D]ISOXAZOL-3-YL)PROPANOIC ACID USEFUL AS KYNURENINE MONOOXYGENASE INHIBITORS |
Description | Compound of formula (I) wherein R1 is heteroaryl either unsubstituted or substituted by methyl, ethyl, halo or =O; and R2 is H, methyl or ethyl; and salts thereof are KMO inhibitors and may be useful in the treatment of various disorders, for example acute pancreatitis, chronic kidney disease, acute kidney disewase, acute kidney injury, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, HIV infection, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure. |
IP Reference | WO2016097144 |
Protection | Patent granted |
Year Protection Granted | 2016 |
Licensed | Commercial In Confidence |
Impact | Licensing/spin-out in progress |
Title | 3-(6-CHLORO-3-OXO-3,4-DIHYDRO-(2H)-1,4-BENZOXAZIN-4-YL) PROPANOIC ACID DERIVATIVES AND THEIR USE AS KMO INHIBITORS |
Description | Compounds of formula (I) wherein: R1 is heteroaryl optionally substituted by methyl, ethyl, halo or =O; and R2 is H, methyl or ethyl. and salts thereof are KMO inhibitors and may be useful in the treatment of various disorders, for example acute pancreatitis, chronic kidney disease, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, HIV infection, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel disease, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure. |
IP Reference | WO2016188827 |
Protection | Patent granted |
Year Protection Granted | 2016 |
Licensed | Commercial In Confidence |
Impact | Licensing/spin-out in progress |
Title | KMO inhibitor portfolio |
Description | A portfolio of small molecule KMO inhibitors and supporting data package arising from our DPAc programme collaboration with GSK |
IP Reference | |
Protection | Patent granted |
Year Protection Granted | 2015 |
Licensed | Yes |
Impact | Licensed to Kynos Therapeutics Ltd in July 2021 for up front cash plus royalty |
Title | KMO inhibitor |
Description | Inhibitor for multiple organ failure triggered by acute pancreatitis. GSK/University of Edinburgh Discovery Partnership With Academia (DPAC Award) |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | A new way of academic industry interaction which has led to a new potential therapy for multiple organ failure in acute pancreatitis |
URL | https://clinicaltrials.gov/show/NCT03245619 |
Company Name | APPRESCI LTD |
Description | Advanced Platform for Precision Science (APPreSci Ltd) develops and commercialises precision medicine technologies for patient use. |
Year Established | 2019 |
Impact | None as yet |
Company Name | KYNOS THERAPEUTICS LTD |
Description | Shell company formed to allow investment discussions around commercialising our KMO inhibitor portfolio |
Year Established | 2020 |
Impact | Pending |
Description | "The Research Landscape in Scotland". Academy of Medical Sciences Careers Day, Glasgow. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | "The Research Landscape in Scotland". Invited lecture. Academy of Medical Sciences Careers Day, Glasgow. |
Year(s) Of Engagement Activity | 2017 |
Description | APPLe - Acute Pancreatitis Patient Liaison |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Ongoing patient support group with engagement in research direction/strategy, grant applications. |
Year(s) Of Engagement Activity | 2017,2018 |
URL | http://www.appresci.com |
Description | APPreSci Patient Stories |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Acute pancreatitis YouTube videos describing the aftermath of an episode of severe acute pancreatitis. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.appresci.com |
Description | Big Data and Infection - invited talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | invited talk at this workshop |
Year(s) Of Engagement Activity | 2017 |
Description | I'm A Scientist Get me Out of Here |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Part of the MRC Festival of Science - I'm A Scientist Get me Out of Here. This was a series of live online interviews and interactions over the course of 3-4 weeks, engaging with schools where pupils were given the opportunity to ask probing questions about science |
Year(s) Of Engagement Activity | 2018 |
URL | http://imascientist.org.uk |
Description | International Molecular Pathology Symposium (IMPS) 2018 0 Invited Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | International Molecular Pathology Symposium (IMPS) 2018 - iNvited lecture |
Year(s) Of Engagement Activity | 2018 |
Description | Let's Talk About Health - Public Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Let's Talk About Health Public Lecture Series |
Year(s) Of Engagement Activity | 2018 |
URL | http://ed.ac.uk/medicine-vet-medicine/news-events/college-events/let-s-talk-about-health-lecture-ser... |
Description | Mechanisms of Pancreatitis-Associated Organ Failure |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar, Blizard Institute, QMUL. |
Year(s) Of Engagement Activity | 2017 |
Description | Target Validation and Drug Discovery for KMO inhibitors |
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 given jointly with GSK colleague at ELRIG 2019, Cambridge UK |
Year(s) Of Engagement Activity | 2019 |