Protecting tendon from lifestyle-induced epigenetic and metabolic alterations

Overview of project

Tendon pain and degeneration afflict many older people, reducing mobility and independence and enforcing a more sedentary lifestyle. Little can be done clinically for ruptured degenerate tendons, making prevention of age-related degeneration an imperative research goal in tendon biology. We observe high levels of advanced glycation end products (AGEs) and upregulated oxidative stress mechanisms like FOXO transcription factors in degenerate rotator cuff tendons, suggesting accumulating metabolic stress. We find that the metabolic hormone cortisol induces premature stress-induced senescence in human tenocytes which is prevented by anabolic therapies like platelet rich plasma or by metabolic approaches like reducing glucose or co-treating with resveratrol, an activator of sirtuin deacetylases. Furthermore, low glucose or resveratrol also reverse stress-induced senescence, providing hope that the damage may not be permanent. In stark contrast, exposure of tenocytes to Type II diabetic levels of glucose increases acetylation of 2 epigenetic marks linked to long-term sugar-induced damage in other tissues. We also find these marks to be highly expressed in degenerate rotator cuff tendons.

In this DPhil project we will:
1. Further define the metabolic damage induced in tenocytes by high glucose.
2. Discover the functional consequences of sugar-induced epigenetic modifications on key transcription factors
3. Assess mitochondrial dysregulation induced by high glucose or GC in tenocytes and test reversibility by our panel of metabolic and anabolic therapies
4. Given that exercise improves both glucose handling and anabolic pathways in skeletal tissues, explore the effect of mechano-loading alone and in combination with our treatment panel.

Eligibility
This three-year research-based DPhil studentship is aimed at basic scientists with an interest in pursuing research in clinically relevant applications of cell signaling and epigenetics. The studentship is full-time with a non-clinical level bursary from Orthopaedic Research UK (formerly Furlong). The studentship is open to UK or EU students who are eligible for home fees. Applicants must have or expect to obtain a first or upper second class (2:i), or equivalent, in their bachelor’s degree. You will also need to provide evidence of competence in English language if English is not your first language.

How to apply
This studentship will be hosted by the Nuffield Dept of Orthopaedics, Rheumatology and Musculoskeletal Sciences and based in the Botnar Research Centre, a dedicated basic science laboratory facility with typically 50 postgraduate research students and excellent clinical links. Information on NDORMS Research and Teaching activities can be found on www.ndorms.ox.ac.uk.

Candidates must apply for both the programme, DPhil in Musculoskeletal Sciences, and the studentship through the University of Oxford online Graduate Application system. The application form, all supporting materials, including references and payment, must be received by the deadline. To access the application guide and form, please visit www.ox.ac.uk/admissions/postgraduate_courses

On the application form, in the section headed ‘Departmental Studentship Applications’, you should indicate that you are applying for a studentship and enter the reference code for this studentship: 2012 MSK/NDORMS-01.