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PhD Research Project: DiMeN Doctoral Training Partnership: An epigenetic approach to healthy ageing

Employer
Global Academy Jobs
Location
United Kingdom
Closing date
Jan 6, 2017

Job Details

Details

Over 60% of people aged over 65 have multiple age-related chronic diseases. The accumulation of deficits resulting from multimorbidity leads to frailty, with loss of independence. Over 80% of the medicare budget in the US is spent on care for frailty and multimorbidity. The current treatment based on targeting each disease individually is not effective due to polypharmacy and the accumulation of side effects. New interventions, which target fundamental ageing processes, and therefore reduce the impact of multimorbidity and frailty, are required(1).

Accumulation of DNA damage with age is one of the main mechanisms of ageing leading to cellular senescence, the accumulation of which is detrimental to tissue maintenance and repair(2). Genetic removal of senescent cells has been shown to reduce onset of multiple age-related diseases, suggesting it is an excellent target for intervention(3). In our previous work we have shown that inhibition of a histone demethylase in aged human mesenchymal stem cells (hMSC) promotes the repair of DNA damage, and reverse senescence. This resulted in the extension of hMSC lifespan. Our hypothesis is that inhibition of this target gene will reduce cellular senescence in an aged mouse, leading to delayed beneficial health outcomes. We have an inducible mouse knock out (www.mousephenotype.org) and shown that conditional ablation of this gene in adult mice leads to over 90% reduction in expression with no adverse effects on the mice.

We plan to determine;

1. The network of genes responsible for the enhanced DNA damage response and involved in the reversal of senescence.

2. Whether ablation of the histone demethylase in ageing mice leads to reversal of accumulation of DNA damage and cellular senescence, particularly in stem cells, and if this results decreased signs of age-related disorders and frailty. We will induce the deletion of the histone demethylase when mice are 18 months of age. When mice starts showing deficits. We will measure the amount of cellular DNA damage and senescence accumulated in tissues by immunostaining using a combination of markers known to identify senescent cells: ɣH2AX and 53BP1, p16, p21, PCNA. These protocols are well established in the laboratory of the primary supervisor. We will assess mice health using the Harwell phenotypic pipeline, to test function across the cardiac, metabolic, immune, musculoskeletal and sensory systems as well employing cognitive and behavioural tests. We will also measure the frailty index which has been established in both supervisors’ laboratory. We will perform a more in depth analysis of the musculoskeletal system by focusing on the analysis of bone for signs of improved bone loss (bone structure by microCT, cellular composition by histomorphometry, bone strength, stem cell function) and reduced osteoarthritis-like signs in the joint (medial plateau trabecular thickness, OARSI score, number of osteophytes) and muscle deterioration (fibre number, size and type, functional stem cell analysis). We will monitor survival and cause of death by necropsy and pathology at the time of sacrifice.

This project is a collaborative effort between the MRC Arthritis Research UK Centre for Integrated Research Into musculoskeletal Ageing (CIMA) at the University of Sheffield and Liverpool and the MRC Harwell Institute. It will provide a unique opportunity for a student to gain experience in cutting edge in vitro and in vivo techniques and take advantage of the facilities and expertise of 3 leading institutions. The supervisors are leading the COST Action MouseAge which brings together researchers from 25 European countries and holds training schools in ageing and interventions. The student will be part of this network with excellent training opportunities. The student will be based in Sheffield but expected to complete approximately a year’s study in Harwell undergoing training in phenotyping and carry out in vivo ageing studies. In addition they will visit Liverpool to learn histological analysis of muscle.

Supervisors:
Professor Ilaria Bellantuono (University of Sheffield)
Dr Paul Potter (MRC Harwell)
Dr Katarzyna Goljanek-Whysall (University of Liverpool)
 

Funding Notes

DiMeN DTP studentships are funded for 3.5 years and include:

- Tax-free maintenance grant set at the UK Research Council's national rate.
- Full payment of tuition fees at the Home/EU rate.
- A Research Training Support Grant to support your research studies.

Successful Home students will receive a full studentship. EU students will be considered for a full studentship/fees only support depending on the excellence of their qualifications and their employment/residency status.

Please carefully read the instructions on eligibility and how to apply at our website and use the link on the page to submit an application: http://www.dimen.org.uk/how-to-apply/application-overview

References

1. Figueira I, Fernandes A, Mladenovic A, Lopez-Contreras A, Henriques CM, Selman C, Ferreiro E, Gonos ES, Trejo JL, Misra J, et al. Interventions for age-related diseases: shifting the paradigm. Mech Ageing Dev. 2016.
2. Childs BG, Durik M, Baker DJ, and van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21(12):1424-35.
3. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, A. Saltness R, Jeganathan KB, Verzosa GC, Pezeshki A, et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184-9.

Company

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