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Hypoxia, inflammation and local steroid metabolism during wound healing: towards a new therapy for diabetic foot ulcers

PGR-P-684

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 Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

Type 2 diabetes is an unmet clinical need of global importance with a growing financial burden. Diabetic foot ulcers, characterized by chronic inflammation and hypoxia, occur in 15-25% per cent of people with diabetes (lifetime risk) and currently affect over 3 million people in the UK. Often, the lack of healing leads to amputation and strikingly up to 80% cent of people with diabetes die within five years of having an amputation or a foot ulcer.

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

<p>Glucocorticoid (GC) hormones are commonly used to treat a range of inflammatory disorders and cause many adverse effects including hyperglycaemia, weight gain, skin thinning, collagen loss, impaired wound healing and increased risk of infection. GC activated by 11&beta;-HSD1 regulate cell functions in tissues such as fat, muscle and liver but the effects of 11&beta;-HSD1 in the skin are poorly understood. Previous research have demonstrated increased 11&beta;-HSD1 activity during normal wound healing and improved wound healing in healthy aged mice lacking 11&beta;-HSD1 but the role of 11&beta;-HSD1 in wound healing impaired by diabetes has not been investigated.</p> <p>Quantitative Polymerase Chain Reaction following mRNA extraction and cDNA synthesis will used to analyse gene expression during wound healing in healthy mice compared to a genetic mouse model of diabetes (leptin-receptor deficient). This will be compared to mice that have been treated with the topical 11&beta;-HSD1 inhibitor carbenoxolone or placebo. Immunohistochemistry will be used to visualise changes in wound healing, inflammation and collagen remodelling.</p> <p>The role of hypoxia will also be investigated by examining the effect of 11&beta;-HSD1 inhibition on wound healing in the presence / absence of an impermeable dressing. This will be complimented by in vivo hypoxia experiments exploring the regulation of angiogenesis by 11&beta;-HSD1 in primary human skin fibroblasts.</p> <h6>This project has the scope to develop a new treatment for diabetic foot ulcers that could improve morbidity and mortality in patients with type 2 diabetes, leading to savings in NHS expenditure of &pound;1 billion annually.<br /> &nbsp;</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</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<br /> &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>

<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>