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: MRC 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.

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.

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.

Publications

10 25 50

 
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 MRC Confidence in Concept
Amount £1,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2019 
End 10/2019
 
Description MRC Doctoral Training Programme in Precision Medicine
Amount £5,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
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 Academic/University
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 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
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 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 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 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 Farr/GSK Epidemiology of Acute Pancreatitis 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Experimental design and expertise in Acute Pancreatitis
Collaborator Contribution Statistical analysis, Epidemiology. Modelling, Data Safe haven
Impact Report on the epidemiology of AP in Scotland.
Start Year 2012
 
Description Farr/GSK Epidemiology of Acute Pancreatitis 
Organisation NHS National Services Scotland (NSS)
Country United Kingdom 
Sector Public 
PI Contribution Experimental design and expertise in Acute Pancreatitis
Collaborator Contribution Statistical analysis, Epidemiology. Modelling, Data Safe haven
Impact Report on the epidemiology of AP in Scotland.
Start Year 2012
 
Description Farr/GSK Epidemiology of Acute Pancreatitis 
Organisation University of Dundee
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental design and expertise in Acute Pancreatitis
Collaborator Contribution Statistical analysis, Epidemiology. Modelling, Data Safe haven
Impact Report on the epidemiology of AP in Scotland.
Start Year 2012
 
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 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
 
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 
 
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 "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 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