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Cellular conversations: stress hormone metabolism as a novel anti-fibrotic target in Giant Cell Arteritis

PGR-P-246

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Sarah Mackie and Dr Ana Tiganescu
Schools
School of Medicine
<h2 class="heading hide-accessible">Summary</h2>

Giant Cell Arteritis (GCA) affects 0.1-1.7% of the UK population with 15,000 new patients each year. The disease is characterised by vascular inflammation that drives arterial wall thickening (hyperplasia), stiffening (fibrosis) and reduced blood flow. Untreated, this can result in blindness that usually prevented by anti-inflammatory glucocorticoid therapy.

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

<p>However, glucocorticoids also promote cardiovascular disease, including arterial hyperplasia and fibrosis. It is unknown whether glucocorticoids can paradoxically drive hyperplasia in the early stages of GCA treatment while suppressing local inflammation and clinical symptoms.</p> <p>The enzyme 11&beta;-hydroxysteroid dehydrogenase type 1 (11&beta;-HSD1) regulates tissue glucocorticoid availability by activating cortisol from cortisone. Inflammation induces 11&beta;-HSD1 activity in a variety of tissues but expression in GCA is unknown. The role of 11&beta;-HSD1 in fibrosis is also unexplored.</p> <p>Objectives - We hypothesize that 11&beta;-HSD1 drives fibrosis by promoting pro-fibrotic macrophage differentiation that may contribute to arterial hyperplasia in GCA.</p> <p>Objective 1: Define 11&beta;-HSD1 expression in GCA</p> <p>Objective 2: Investigate 11&beta;-HSD1 as a mediator of pro-fibrotic signalling</p> <p>Objective 3: Determine effects of 11&beta;-HSD1 inhibition on vascular dysfunction in vivo</p> <p>Work Package (WP) 1 (October 2020-September 2021): Immunohistochemistry training by the Leeds Virtual Pathology Facility, RNA extraction from paraffin-embedded sections and a possible immunohistochemistry-focused placement at AstraZeneca laboratories (Objective 1).</p> <p>WP2 (October 2021-March 2022): Tissue culture training and 11&beta;-HSD1 characterization during macrophage differentiation (Objective 2).</p> <p>WP3 (April 2022 &ndash; March 2023): Characterization of mesenchymal-immune cross-talk and pro-fibrotic effects mediated by 11&beta;-HSD1 (Objective 2). Transcriptomics training (Leeds Immunogenetics Facility). Home Office Personal Licence training.</p> <p>WP4 (April 2023 &ndash; November 2023): In vivo experiments (Objective 3).</p> <p>WP5 (December 2023 &ndash; March 2024): Publication / thesis write-up and dissemination.</p> <p>The project benefits from access to clinical samples and may include a placement in industry with AstraZeneca. Further clinical opportunities may also be possible through the translational aspects of this project.</p> <p><strong>References</strong></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>Harris E, Tiganescu A, Tubeuf S, Mackie SL.The prediction and monitoring of toxicity associated with long-term systemic glucocorticoid therapy. Curr Rheumatol Rep. 2015 Jun;17(6):513.</p> <p>Michailidou Z, Turban S, Miller E, Zou X, Schrader J, Ratcliffe PJ, Hadoke PW, Walker BR, Iredale JP, Morton NM, Seckl JR. Increased angiogenesis protects against adipose hypoxia and fibrosis in metabolic disease-resistant 11&beta;-hydroxysteroid dehydrogenase type 1 (HSD1)-deficient mice. J Biol Chem. 2012 Feb 3;287(6):4188-97.</p> <p>Jakobsson K, Jacobsson L, Mohammad AJ, Nilsson J&Aring;, Warrington K, Matteson EL, Turesson C. The effect of clinical features and glucocorticoids on biopsy findings in giant cell arteritis. BMC Musculoskelet Disord. 2016 Aug 24;17(1):363.</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&nbsp;<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:<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>