DEMISTIFI Multi Morbidity: DEfining MechanIsms Shared across mulTI-organ FIbrotic disease to prevent the development of long term multi-morbidity
Lead Research Organisation:
University of Nottingham
Department Name: School of Medicine
Abstract
Scarring (fibrosis) affects every organ in the body and has been estimated to cause approximately one third of all deaths world-wide. Scarring classically affects the lungs and liver in response to environmental injury such as cigarette smoke, industrial dusts (eg asbestos) and alcohol. However, scarring also affects the heart and kidneys leading to heart and renal failure, the bone marrow leading to blood disease, the pancreas leading to diabetes, the blood vessels leading to strokes and heart attacks and the brain in multiple sclerosis and motor neurone disease. Multi-morbid fibrotic disease defines groups (clusters) of conditions that occur together and are characterised by scarring in various organs. Some are known such as short telomere syndromes leading to liver, lung and bone marrow scarring and connective tissue disease related scarring in muscle and joint disease. However, many scarring clusters are not well recognised (eg lung fibrosis and diabetes) and it is possible that there are completely unknown clusters that may reflect distinct genetic or environmental risk factors for scarring.
Scarring is often progressive, notably in the lungs, liver and kidneys where it frequently leads to death or the need for organ transplantation. In some cases if the environmental trigger can be removed the scarring will stop, or even improve, but in other situations the scarring will progress regardless of whether the environmental cause is removed. This may reflect advanced disease which is 'beyond repair' or specific genetic interactions with the environmental triggers.
The aim of this proposal is to understand how genetic and environmental risk factors interact to promote the development of progressive fibrosis across a number of different organs. These studies will address a focused question which will define which groups of scarring diseases are linked by genes that cause telomeres to shorten and cause premature ageing, and are known to be responsible for the known cluster of lung liver and bone marrow scarring. We will investigate the interaction between these genes and known environmental triggers including cigarette, alcohol and dusts as well as other triggers that may not yet have been identified. We will determine whether the biological pathways which are responsible for lung, liver or bone marrow fibrosis may also lead to scarring in other organs and whether they link expanded clusters of scarring involving the lung, liver, pancreas, kidney, bone marrow, brain, heart, gastrointestinal tract, or whether there are other genes that promote different clusters of scarring disease.
We will then investigate whether medicines that are known to protect against certain fibrotic diseases within these clusters (for example metformin for diabetes and simvastatin for heart disease and stroke) might have beneficial affects across the full spectrum of fibrotic disease by targeting disease pathways that are shared across the different organs.
These studies will require a collaboration between academics and clinicians with expertise in studying populations, genetics, cells, specific diseases, radiology, and 'big data' analysis to take a team science approach to solving a very important and challenging problem. The DEMISTIFI consortium will provide the expertise to deliver the evidence needed to understand multi organ scarring to improve treatment approaches that will help prevent this devastating scarring process throughout the body.
Scarring is often progressive, notably in the lungs, liver and kidneys where it frequently leads to death or the need for organ transplantation. In some cases if the environmental trigger can be removed the scarring will stop, or even improve, but in other situations the scarring will progress regardless of whether the environmental cause is removed. This may reflect advanced disease which is 'beyond repair' or specific genetic interactions with the environmental triggers.
The aim of this proposal is to understand how genetic and environmental risk factors interact to promote the development of progressive fibrosis across a number of different organs. These studies will address a focused question which will define which groups of scarring diseases are linked by genes that cause telomeres to shorten and cause premature ageing, and are known to be responsible for the known cluster of lung liver and bone marrow scarring. We will investigate the interaction between these genes and known environmental triggers including cigarette, alcohol and dusts as well as other triggers that may not yet have been identified. We will determine whether the biological pathways which are responsible for lung, liver or bone marrow fibrosis may also lead to scarring in other organs and whether they link expanded clusters of scarring involving the lung, liver, pancreas, kidney, bone marrow, brain, heart, gastrointestinal tract, or whether there are other genes that promote different clusters of scarring disease.
We will then investigate whether medicines that are known to protect against certain fibrotic diseases within these clusters (for example metformin for diabetes and simvastatin for heart disease and stroke) might have beneficial affects across the full spectrum of fibrotic disease by targeting disease pathways that are shared across the different organs.
These studies will require a collaboration between academics and clinicians with expertise in studying populations, genetics, cells, specific diseases, radiology, and 'big data' analysis to take a team science approach to solving a very important and challenging problem. The DEMISTIFI consortium will provide the expertise to deliver the evidence needed to understand multi organ scarring to improve treatment approaches that will help prevent this devastating scarring process throughout the body.
Technical Summary
Organ fibrosis accounts for approximately one third of all deaths world-wide. It is associated with aging and metabolic abnormalities that occur in response to a range of known and unknown genetic and environmental factors. Understanding shared pathogenic mechanisms, especially in early disease, may identify specific clusters of disease that will respond to repurposing of available therapies. Common genetic, environmental, lifestyle and socioeconomic factors or biological pathways that link these mechanistic clusters aren't readily recognised by conventional disease and organ centred approaches. Focusing on the mechanistic basis fibrosis offers a unique opportunity to recognise early disease, identify disrupted mechanisms and repurpose disease specific drugs to instead target the underlying pathological process.
We will use a multi-disciplinary approach to identify clusters of multi-morbid fibrotic (MMF) disease and identify common pathogenic mechanisms underlying these clusters. This will be achieved using available datasets and UK Biobank data to develop genetic risk prediction strategies which identify important clinical outcomes such as disability and premature death. We will use these data to inform: a) The development of the DEMISTIFI cohort of patients at risk of MMF disease, who will be deeply phenotyped for development of pre-symptomatic multi organ fibrosis using genetics and imaging characteristics of multiple organs linked to physiology and pathobiology. b) Mechanistic studies that will identify opportunities to intervene in the key pathways to influence the natural history of the cluster to benefit patient care.
We will bring together a diverse group of researchers to identify the environmental, geographical, and socio-economic factors that interact with genetic determinants and molecular pathways promoting disease to ensure a 'team science' approach that can identify and intervene in MMF diseases in the areas of greatest need.
We will use a multi-disciplinary approach to identify clusters of multi-morbid fibrotic (MMF) disease and identify common pathogenic mechanisms underlying these clusters. This will be achieved using available datasets and UK Biobank data to develop genetic risk prediction strategies which identify important clinical outcomes such as disability and premature death. We will use these data to inform: a) The development of the DEMISTIFI cohort of patients at risk of MMF disease, who will be deeply phenotyped for development of pre-symptomatic multi organ fibrosis using genetics and imaging characteristics of multiple organs linked to physiology and pathobiology. b) Mechanistic studies that will identify opportunities to intervene in the key pathways to influence the natural history of the cluster to benefit patient care.
We will bring together a diverse group of researchers to identify the environmental, geographical, and socio-economic factors that interact with genetic determinants and molecular pathways promoting disease to ensure a 'team science' approach that can identify and intervene in MMF diseases in the areas of greatest need.
Organisations
- University of Nottingham (Lead Research Organisation)
- AstraZeneca (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- University College London (Collaboration)
- University of Manchester (Collaboration)
- UNIVERSITY OF NOTTINGHAM (Collaboration)
- Bristol-Myers Squibb (Collaboration)
- Nordic Bioscience (Collaboration)
- Genentech, Inc (Collaboration)
- UNIVERSITY OF EXETER (Collaboration)
Publications
Jafari M
(2022)
LMISA: A lightweight multi-modality image segmentation network via domain adaptation using gradient magnitude and shape constraint.
in Medical image analysis
Jenkins G
(2020)
Demystifying pulmonary fibrosis.
in American journal of physiology. Lung cellular and molecular physiology
Massen G
(2023)
Response to: Consensus and agreements on the classification of fibrotic diseases
in QJM: An International Journal of Medicine
Massen GM
(2023)
Classifying the unclassifiable-a Delphi study to reach consensus on the fibrotic nature of diseases.
in QJM : monthly journal of the Association of Physicians
May J
(2023)
Beyond epithelial damage: vascular and endothelial contributions to idiopathic pulmonary fibrosis.
in The Journal of clinical investigation
Mohammadi-Nejad A
(2022)
Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk
Description | Defining the anti-fibrotic mechanisms of prostacyclin drugs in pulmonary fibrosis |
Amount | £289,656 (GBP) |
Funding ID | MR/X001814/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2023 |
End | 04/2026 |
Description | Multi-Modal |
Amount | £1,000,000 (GBP) |
Funding ID | MR/W031469/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2022 |
End | 09/2025 |
Title | DEMISTIFI datasets LUNG, LIVER, PANCREAS and INTESTINE |
Description | LUNG, LIVER, PANCREAS and INTESTINE datasets have been added to the HDR Gateway |
Type Of Material | Database/Collection of data |
Year Produced | 2024 |
Provided To Others? | No |
Impact | Some of the datasets that make up the DEMISTIFI dataset have lead to published outputs but the joint assessment is currently underway |
Title | Longitudinal analysis of lung function |
Description | Imputation technique to maximise the analytical capabilities despite missing data. |
Type Of Material | Computer model/algorithm |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Work has been cited by others. |
Title | PROFILE Study database |
Description | We have a collection of over 330 biological samples with matched clinical data from patients with incident IPF |
Type Of Material | Database/Collection of data |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | First paper is under review at Lancet and further papers are planned. A number of lectures describing the PROFILE cohort have been delivered and two articles have cited the development of the PROFILE cohort. |
Description | DEMISTIFI Consortium |
Organisation | AstraZeneca |
Department | MedImmune |
Country | United Kingdom |
Sector | Private |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | DEMISTIFI Consortium |
Organisation | Bristol-Myers Squibb |
Country | United States |
Sector | Private |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | DEMISTIFI Consortium |
Organisation | Genentech, Inc |
Country | United States |
Sector | Private |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | DEMISTIFI Consortium |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | DEMISTIFI Consortium |
Organisation | University of Exeter |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | DEMISTIFI Consortium |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | DEMISTIFI Consortium |
Organisation | University of Nottingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | DEMISTIFI Consortium |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I established the development of a multi-organ fibrosis consortium to try and prevent the development of multi morbidity. |
Collaborator Contribution | There are a number of partners involved in this consortium including genetic epidemiologist, MRI physicists, clinicians, fundamental biologists and data scientists as well as patient public representatives and also industry partners. These partners bring a wealth of expertise and resources to the collaboration. |
Impact | DEMISTIFI collaboration bid submitted. |
Start Year | 2020 |
Description | Matrix Neo-epitope analysis |
Organisation | Nordic Bioscience |
Country | Denmark |
Sector | Private |
PI Contribution | We provided samples and phenotypic know-how to help sample analysis |
Collaborator Contribution | Partner brought scientific and biomarker expertise to assay biomarkers in our patients. |
Impact | This collaboration has lead to a number of publications in high impact journals and continued analysis of samples from our patients. |
Start Year | 2013 |
Description | Cambridge Respiratory Research Seminars, University of Cambridge, UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk entitled Understanding Pulmonary Fibrosis in the Post COVID World |
Year(s) Of Engagement Activity | 2021 |
Description | Clinical Lecture: Scar Wars: A New Hope |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Clinical grand rounds at the Mayo Clinic |
Year(s) Of Engagement Activity | 2024 |
Description | DEMISTIFI Collaboration day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Approximately 60 partners of the DEMISTIFI consortium attended a day long meeting to update the consortium on progress that had been made. This included short research talks and talks from people with lived experience. This sparked discussions throughout the day and lead to inclusion of fibrotic MultiMorbidity in an Imperial College London application for Centre of Research Excellence application. |
Year(s) Of Engagement Activity | 2023 |
Description | DEMISTIFI Multimorbidity |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This was a regional meeting organised by the Royal College of Physicians and Surgeons of Glasgow and it sparked considerable debate about early detection of IPF |
Year(s) Of Engagement Activity | 2024 |
Description | Discovery Medicine Clinical Insight Session, GlaxoSmithKline |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Industry/Business |
Results and Impact | Provided a zoom lecture to GSK about how the learnings from COVID19 may inform future studies in IPF entitled "What can the COVID-19 pandemic teach us about Idiopathic Pulmonary Fibrosis?" Lots of positive feedback and questions asked. |
Year(s) Of Engagement Activity | 2022 |
Description | European IPF Patient Summit COVID-19 and Pulmonary Fibrosis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Gave Webibar about Post COVID lung fibrosis to the European Pulmonary Fibrosis summit to patients with pulmonary fibrosis and their career throughout Europe. |
Year(s) Of Engagement Activity | 2020 |
Description | European Respiratory Society, meeting Munich, Germany. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Gave a talk entitled "Biomarker discovery, development, and implementation in interstitial lung disease" to the European Respiratory Society annual meeting via zoom. |
Year(s) Of Engagement Activity | 2021 |
Description | Gordon Research Conference one Alveolar Repair and Regeneration |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Gave a talk entitled "Alveolar Injury and the Development of Post COVID Fibrosis." which lead to considerable engagement and a new collaboration. |
Year(s) Of Engagement Activity | 2021 |
Description | KUCI meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Annual Kings College London, University College London and Imperial College London (KUCI) Respiratory Society meeting Brockenhurst, UK. |
Year(s) Of Engagement Activity | 2021 |
Description | Oxford Respiratory Summit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation on Idiopathic Pulmonary Fibrosis |
Year(s) Of Engagement Activity | 2020 |
Description | Pulmonary and Critical Care Grand Rounds, University of Birmingham Alabama. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Visiting Professor (via Zoom) at the University of Birmingham, Alabama, USA and had a series of one to one meetings with potential collaborators and gave lecture at the the Univesirty of Alabama Ground Rounds. |
Year(s) Of Engagement Activity | 2021 |
Description | Saudi 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 | I gave a talk to about 50 physicians and researchers from the Middle East abotu the causes, consequnces and management of ILD sparking considerable debate and discussion. |
Year(s) Of Engagement Activity | 2023 |
Description | Series of lectures and workshops at the ILD Summit (Boston USA) |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | The ILD Summit is an annual meeting for the pharmaceutical industry who have a strategic interest and are developing therapeutics for Interstitial Lung Diseases. I chaired two work shops, I was involved in a panel discussion and gave a plenary talk. There were 100 delegates and there was considerable discussion and subjects relevant to improving outcomes for pulmonary fibrosis. |
Year(s) Of Engagement Activity | 2023 |
Description | Snyder Endowed Seminar, University of Calgary |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A visit to the University of Calgary which sparked considerable questions and discussion afterwards |
Year(s) Of Engagement Activity | 2023 |
Description | The Annual Margaret Turner Warwick Lecture and Inaugural Lecture for the MTW Centre for Fibrosing Lung Diseases, Imperial College, London, UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Annual lecture entitled: curing the incurable. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=K6rgn8P_1fI |
Description | Wright-Fleming Institute Infection and Immunity seminar St Mary's Hospital Imperial College London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Gave a talk via Teams to researchers entitled 'Understanding Pulmonary Fibrosis in the Post COVID World.' lots of questions and requests for face to face follow-up visits. |
Year(s) Of Engagement Activity | 2022 |