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  • Project No: NDORMS 2023/5
  • Intake: 2023

PROJECT OVERVIEW

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.

 

TRAINING OPPORTUNITIES

Our dept (NDORMS) has a dedicated training programme for D,Phil students including technical, ethical sessions, and clear indications of support networks within NDORMS and across MSD. Direct supervision is provided by primary supervisor and immediate research group, alongside supporting supervisors and thesis committee. This includes use of new and established techniques e.g. cellular culture and imaging, sequencing prep and analysis, CETSA including mass spec processing and bioinformatic analysis, and training courses through established core facilities.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. All students are also required to attend a 2-day Statistical and Experimental Design course at NDORMS.Students will also be required to attend regular seminars within the Department and have access to a variety of other courses run by the Medical Sciences Division Skills Training Team https://www.medsci.ox.ac.uk/study/skillstraining and the wider University.

 

KEY PUBLICATIONS

  1. HS Han, I Jun, HK Seok, KS Lee, K Lee, F Witte, D Mantovani, YC Kim, S Glyn‐Jones, JR Edwards. Biodegradable Magnesium Alloys Promote Angio‐Osteogenesis to Enhance Bone Repair. Advanced Science. 23 June 2020: https://doi.org/10.1002/advs.202000800
  1. Rothweiler EM. et al. Covalent fragment-based ligand screening approaches for identification of novel ubiquitin proteasome system modulators (2022), Biological Chemistry, 403, 391 – 402.
  2. Whitburn J. et al. Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival. Sci Adv. 2022 Feb 25;8(8):eabf9096. doi: 10.1126/sciadv.abf9096.

 

KEYWORDS

Ageing, Multimorbidity, Genomics, Proteomics

 

HOW TO APPLY

The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the NDORMS Graduate Studies Team (graduate.studies@ndorms.ox.ac.uk) who will be able to advise you of the essential requirements.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable).

The application guide and form is found online and the DPhil or MSc by research will commence in October 2023.

Applications should be made to one of the following programmes using the specified course code:

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

MSc by research in Molecular and Cellular Medicine (course code: RM_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.