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EcMagine': Extracellular Matrix ageing across the life course interdisciplinary research network

Reference	BB/W018314/1
Principal Investigator / Supervisor	Dr Elizabeth Laird
Co-Investigators / Co-Supervisors	Professor Matthew Dalby, Dr Vanja Pekovic-Vaughan, Dr Daryl Shanley, Dr Joe Swift, Dr Lisa White
Institution	University of Liverpool
Department	Musculoskeletal & Ageing Science
Funding type	Research
Value (£)	176,276
Status	Current
Type	Research Grant
Start date	14/02/2022
End date	13/02/2024
Duration	24 months

Abstract

Ageing leads to progressive decline in metabolic/behavioural/physiological functions, leading to reduced healthspan. Across the world, numbers of people >65 are increasing 3 times faster than those <15. >65s will make up >25% of UK population in 50 years, with regional health inequalities exacerbating disparities in healthspan. Our network focusses on the ageing of extracellular matrix (ECM), a major structural & functional determinant of tissue resilience with remarkable tissue specificity. Our tissues comprise of cells and >1000 ECM proteins. The ECM facilitates cell-matrix and cell-cell communication, and exchange of nutrients and growth factors. The ECM undergoes structural changes with age, leading to accumulation of fragmented, cross-linked ECM proteins and loss of ECM ligands. Alterations to ECM underpin many age-related tissue changes, such as loss of elasticity, poor healing, scarring, abnormal growths and entry into senescence, a hallmark of ageing. Remarkably, ECM is a target of daily changes governed by our ~24h (circadian) time-keeping mechanisms, highlighting ECM as a malleable driver of tissue ageing. However, there is a critical need to understand how ageing alters the ECM of specific organ/tissue systems, how age-associated ECM impacts tissue-specific deterioration and the roles of specific cell sub-types involved. The EcMagine Northern-led Ageing Network brings together complementary expertise in key aspects of ageing, matrix biology, chronobiology, AI/computational modelling and tissue engineering across UK to develop novel models to study ECM ageing, particularly 3D biological models, new biomaterials to mimic tissue-specific ECM and in silico models to predict novel anti-ageing therapies. Working together, sharing models, technologies, knowledge and expertise, we will strategically address challenges in ageing research and generate paradigm-shifting discoveries with long-term benefit of improving lives and outcomes for older people.

Summary

Advances in science, medicine and living conditions mean that people are living longer. Whilst a longer life brings exciting opportunities, ageing is too often associated with ill health and frailty. The ageing demographic brings with it a steep increase in the public burden of health and social care as well as financial challenges for pension funds. Across the UK, and globally, there are inequalities in the lived experience of ageing, with social demographics, life course experiences and genetic factors influencing stark disparities between chronological and biological age in different populations. Our application focusses on the ageing of extracellular matrix (ECM), the main structural component of tissues and organs. The ECM is a three-dimensional network of molecules which not only provides resilience to all tissues in the body, but also controls key biophysical signals to support vital cell functions. The ECM makes up a large fraction of many tissues; for example, in the bone, the ECM is mineralised providing essential strength, whilst in the lung, it provides elasticity necessary for normal function. The ECM in each organ is very distinct and very dynamic, responding to various external factors such as day/night cycles, highlighting its malleability. With age, ECM deteriorates through a process influenced by an imbalance between its production and turnover, chemical changes to molecules as well as changes in its relationship with our cells. Importantly, ECM deterioration with age directly influences key functions of cells and tissues in our body leading to abnormal communication between our cells and loss of vital functions, which contributes to many age-related diseases. Studying ECM ageing across the life course poses particular challenges due to differences between model organisms and humans, the limitations of using standard 2-dimensional culturing of isolated cells and difficulties in accessing healthy human tissues. Fortunately, using approaches in material science and tissue engineering to develop humanised cell models with organ-specific ECM scaffolds has enormous potential for high-throughput mechanistic and drug screening studies to target age-related ECM degradation and combat hallmarks of cellular ageing, thus offering novel, more effective and safer solutions. We propose a new interdisciplinary ageing network bringing together biologists, chemists, geneticists, ageing scientists, engineers, mathematicians, health and social scientists and clinicians. The network will be led by investigators at the Universities of Liverpool, Glasgow, Manchester, Nottingham and Newcastle but will operate across the whole of UK. We will engage industry stakeholders and technology providers in the network events and liaise with the public and local charities through to research experts on the external advisory panel. A key focus of the network will be increasing the knowledge of this new interdisciplinary field, facilitating sharing of technologies for rapid discoveries and pioneering new models to study ageing. Our network will provide informed recommendations for future research to address inequalities influencing ECM ageing. The network will act to increase capacity and diversity in the field through pump-priming activities, network events and incorporating diversity and inclusivity in network activities. The network will operate via a website interface facilitating member registration and communication. Communications will be supported by newsletters, social media and network events. More broadly, the network will interface with relevant research societies, related networks, doctoral training partnerships and technician development centres. Working together, sharing models, technologies, knowledge and expertise, our unique approach will generate paradigm-shifting discoveries with long-term benefits for discovery science, industry and medicine to improve lives of older people.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Ageing Interdiciplinary Research Network [2021]
Funding Scheme	X – not Funded via a specific Funding Scheme

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