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Regulation of skin function and wound healing by pre-receptor glucocorticoid metabolism in diet-induced animal models of diabetes

PGR-P-685

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Ana Tiganescu
Additional supervisors
Dr David Russell
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Cardiovascular and Metabolic Medicine
<h2 class="heading hide-accessible">Summary</h2>

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 (&amp;pound;12.4 billion) on treating diabetes, including &amp;pound;1 billion on diabetic foot ulcer treatment.

<h2 class="heading hide-accessible">Full description</h2>

<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 (11&beta;-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 11&beta;-HSD1 improves wound healing in mice with diabetes</li> <li>Understand how 11&beta;-HSD1 affects wound healing (such as changes in blood clotting) in mice with diabetes</li> <li>Compare 11&beta;-HSD1 levels in healthy and diabetic human skin</li> <li>Examine how 11&beta;-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 11&beta;-HSD1-null (HSD11B1-KO) mice with and without high-fat / high-fat high-sucrose diet-induced diabetes. This essential pre-clinical testing of 11&beta;-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 11&beta;-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 11&beta;-HSD1 inhibitor AZ13076781 will differentiate between systemic and local effects of 11&beta;-HSD1 inhibition to inform further clinical development of topical preparations.</p> <p>Work Package 3: 11&beta;-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 11&beta;-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 11&beta;-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 11&beta;-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&nbsp;</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 11&beta;-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice. Endocrinology. 2018, 159(1):547-556</p> <p>&nbsp;</p>

<h2 class="heading">How to apply</h2>

<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. To apply for this project applicants should complete a<a href="https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form"> Faculty Application Form</a> and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If you have already applied for other projects using the Faculty Application Form this academic session you do not need to complete this form again. Instead you should email fmhgrad to inform us you would like to be considered for this project.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p>&nbsp;</p>

<h2 class="heading heading--sm">Entry requirements</h2>

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.

<h2 class="heading heading--sm">English language requirements</h2>

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 Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; 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.

<h2 class="heading">Contact details</h2>

<p>For further information please contact the Graduate School Office<br /> e:&nbsp;<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a> t: +44 (0)113 343 8221</p>


<h3 class="heading heading--sm">Linked research areas</h3>