Revealing mechanism and functionality of new and old agents in multi-morbidity research using a multi-omics approach
LEAD SUPERVISOR: Professor James Edwards, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences
Co-supervisor: Professor Kilian Huber, Nuffield Department of Clinical Medicine
Commercial partner: Medicines Discovery Catapult, Macclesfield
By the year 2040 approximately 1 in 7 people in the UK is projected to be over the age of 65, however the observed increases in lifespan over the last 100 years have outpaced those in healthspan. Both University of Oxford and Medicines Discovery Catapult are part of the UK SPINE knowledge exchange partnership; a network bringing together multidisciplinary expertise from a range of academia, industry and charity partners to more effectively treat age-related diseases and importantly to target multimorbidities of ageing.
A multicentre drug repurposing pipeline and collaborative team (including above) established through seed-funding from the Oxford-led UKSPINE Ageing Network (Research England) and utilising treated human patient samples, cellular screening assays and multiplex proteomics, has confirmed new potential for the well-established bisphosphonate (BP) class of drug. BPs have represented the frontline treatment for disorders of excessive bone loss for decades, are accessible, affordable, and well-tolerated. Importantly, our work and ongoing clinical studies have revealed BPs reduce risk of a number of ageing-related pathologies including cardiovascular disease, infection, cancer.
This proposal will reveal established/novel agents with potential to target multiple morbidities, continue efforts exploring BPs as an exemplar of this approach to reveal how BPs act in non-skeletal tissues to prevent onset of disease.
Building upon existing screening techniques where cell/tissue types and specific clinically-utilised and novel BPs and have been prioritised for further investigation, this project will determine i) how BPs (ZOL, ALN, CLO, OX-14) increase cell proliferation and protect against ageing-linked challenges (oxidative stress, onset of senescence) in cardiomyoblasts, hepatocytes and macrophages in vitro utilising a range of cellular and molecular techniques including fluoro-imaging of tagged BPs, RNA and ATAC seq, and live cell imaging. New targets for BP action will be explored by Cellular Thermal Shift Assay, with unknown proteins identified using mass spectrophotometry, and cellular validation confirmed in human cell types using standard pharmacological and molecular manipulation (e.g. CRISPR). Data sets will be probed alongside our existing BP-treated patient secretome profiles; ii) local effects of BP treatment in old/young mice will be analysed using spatial transcriptomics (as developed at MDC) to determine senescence and ageing-linked tissue changes over time, confirm a protective impact of BPs and reveal and/or confirm involvement of new targets.
Apply using course: DPhil in Molecular and Cellular Medicine