- Type of research degree
- 4 year PhD
- Application deadline
- Ongoing deadline
- Country eligibility
- International (outside UK)
- Dr Ana Tiganescu
- Additional supervisors
- Dr David Russell
- School of Medicine
- Research groups/institutes
- Leeds Institute of Cardiovascular and Metabolic Medicine
Diabetes is a common disease resulting in a long-term increase in blood sugar levels. Current estimates suggest 1 in 10 people globally will be diagnosed with diabetes by 2040. Diabetes slows wound healing which leads to chronic ulcers, infection and amputation. The NHS spends 10% of its annual budget (£12.4 billion) on treating diabetes, including £1 billion on diabetic foot ulcer treatment.
<p>Cortisol is a hormone produced by the body in response to stress. Cortisol is also used to treat inflammatory diseases such as eczema or lung disease, but long-term steroid use causes side-effects including poor wound healing. Skin contains an enzyme (11β-HSD1) that activates cortisol. Blocking this enzyme improves wound healing in older mice and in mice treated with cortisol but the effect on wound healing in diabetes is unknown.</p> <p>Based at the University of Leeds and working with international experts in diabetes, cortisol function and skin biology, this project aims to:</p> <ol> <li>Test whether the blocking of 11β-HSD1 improves wound healing in mice with diabetes</li> <li>Understand how 11β-HSD1 affects wound healing (such as changes in blood clotting) in mice with diabetes</li> <li>Compare 11β-HSD1 levels in healthy and diabetic human skin</li> <li>Examine how 11β-HSD1 affects structure and function of healthy and diabetic human skin</li> </ol> <p>This work will help develop exciting new treatments that could change the lives of patients with diabetes who suffer from long term, debilitating wounds whilst contributing to substantial savings for the NHS.</p> <p>Work Package 1: Gene expression, skin structure and wound healing in wild-type and transgenic 11β-HSD1-null (HSD11B1-KO) mice with and without high-fat / high-fat high-sucrose diet-induced diabetes. This essential pre-clinical testing of 11β-HSD1 blockade on wound healing of diabetic mouse skin, comparison to healthy skin and degree of normalization will support re-purposing of clinic-ready oral 11β-HSD1 inhibitors as novel therapies for wound healing in diabetes.</p> <p>Work Package 2: Complementary studies in high-fat high-sucrose mice treated with the topical selective AstraZeneca mouse 11β-HSD1 inhibitor AZ13076781 will differentiate between systemic and local effects of 11β-HSD1 inhibition to inform further clinical development of topical preparations.</p> <p>Work Package 3: 11β-HSD1 activity, expression and localization in skin from patients with diabetes compared to healthy controls. This will generate the first ex vivo proof-of-concept data for future human studies.</p> <p>Work Package 4: Confirmatory in vitro studies to examine 11β-HSD1-mediated regulation of key wound healing elements (e.g. angiogenesis and coagulation) in skin from patients with diabetes compared to healthy controls. This will utilise the selective AstraZeneca human 11β-HSD1 inhibitor AZD4017 for mechanistic exploration.</p> <h6>The project benefits from significant consumables funding from an Academy of Medical Sciences Springboard Award and will include opportunities to work in a laboratory in Valencia (Spain) for several weeks as well as a possible placement in industry with AstraZeneca.</h6> <p>References</p> <p>Tiganescu A, Walker EA, Hardy RS, Mayes AE, Stewart PM. Localization, age- and site-dependent expression, and regulation of 11β-hydroxysteroid dehydrogenase type 1 in skin. J Invest Dermatol. 2011 Jan;131(1):30-6.</p> <p>Tiganescu A, Tahrani AA, Morgan SA, Otranto M, Desmouliere A, Abrahams L, Hassan-Smith Z, Walker EA, Rabbitt EH, Cooper MS, Amrein K, Lavery GG and Stewart PM. 11beta-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest. 2013, 123(7), pp.3051-60 </p> <p>Tiganescu A, Hupe M, Uchida Y, Mauro T, Elias PM and Holleran WM. Increased glucocorticoid activation during mouse skin wound healing. J Endocrinol. 2014, 221(1), pp.51-61</p> <p>Tiganescu A, Hupe M, Uchida Y, Mauro T, Elias PM, Holleran WM. Topical 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice. Endocrinology. 2018, 159(1):547-556</p> <p> </p>
<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support your application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme’s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Cardiovascular and Metabolic Disease as your programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul> <p> </p>
A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.
Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.
<p>For further information please contact the Faculty Graduate School<br /> e: <a href="mailto:firstname.lastname@example.org">email@example.com</a></p>
<h3 class="heading heading--sm">Linked research areas</h3>