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

Summary

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.

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.

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates tissue glucocorticoid availability by activating cortisol from cortisone. Inflammation induces 11β-HSD1 activity in a variety of tissues but expression in GCA is unknown. The role of 11β-HSD1 in fibrosis is also unexplored.

Objectives - We hypothesize that 11β-HSD1 drives fibrosis by promoting pro-fibrotic macrophage differentiation that may contribute to arterial hyperplasia in GCA.

Objective 1: Define 11β-HSD1 expression in GCA

Objective 2: Investigate 11β-HSD1 as a mediator of pro-fibrotic signalling

Objective 3: Determine effects of 11β-HSD1 inhibition on vascular dysfunction in vivo

Work Package (WP) 1: 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).

WP2: Tissue culture training and 11β-HSD1 characterization during macrophage differentiation (Objective 2).

WP3: Characterization of mesenchymal-immune cross-talk and pro-fibrotic effects mediated by 11β-HSD1 (Objective 2). Transcriptomics training (Leeds Immunogenetics Facility). Home Office Personal Licence training.

WP4: In vivo experiments (Objective 3).

WP5: Publication / thesis write-up and dissemination.

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.

References

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.

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.

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 11β-hydroxysteroid dehydrogenase type 1 (HSD1)-deficient mice. J Biol Chem. 2012 Feb 3;287(6):4188-97.

Jakobsson K, Jacobsson L, Mohammad AJ, Nilsson JÅ, 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.

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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.