DEMISTIFI Multi Morbidity: DEfining MechanIsms Shared across mulTI-organ FIbrotic disease to prevent the development of long term multi-morbidity

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.

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.