Project ID CM-HD2023_07

ThemeCM-HD

Co Supervisor 1A Dept of Medical and Molecular Genetics/School of Basic and Molecular Biosciences/CAG: Genetics, Rheumatology, Infection, Immunology and DermatologyWebsite

Co Supervisor 1B St John’s Institute of Dermatology/School of Basic and Molecular Biosciences/CAG: Genetics, Rheumatology, Infection, Immunology and DermatologyWebsite

Investigating immuno-metabolism in pustular psoriasis, a single-cell approach

Background: Palmoplantar pustulosis (PPP) is a severe and disabling immune-mediated disease, presenting with painful pustular eruptions on the palms and soles. PPP has a profound impact on quality of life and is very difficult to treat, as its causes are poorly understood.  

We have recently identified a subset of PPP patients harbouring deleterious sequence variants in a gene that is essential to mitochondrial function. Given T-cell activation is dependent on metabolic reprogramming, we anticipate that these PPP alleles will disrupt immune homeostasis. 

Aim: The aim of this project is to characterise the impact of the newly identified PPP alleles, so that we can better understand the broader role of mitochondrial respiration defects in pathological T cell activation. 

Techniques/skills: The consequences of disease alleles will be investigated by combining in-vitro assays with scRNA-seq and flow-cytometry studies of patient T-cells. The student will therefore acquire both experimental and computational skills.  

Intermediate objectives:
1. In year 1, the student will determine the effects of disease alleles on protein stability by combining computational pathogenicity predictions, modelling of 3D protein structure and over-expression of mutant constructs in immortalised cell lines 
2. In year 2, the student will complete in-vitro studies by characterising the impact of disease alleles on protein subcellular localization and mitochondrial function 
3. In year 3, the student will use flow-cytometry and scRNA-seq based methods to characterise patient T cells, derived from blood and skin.
4. In year 4, the student will complete the above experiments and correlate the results with metabolism abnormalities, measured by assessing oxygen consumption rates in patient T cells.

One representative publication from each co-supervisor:

• McCluskey D, Benzian-Olsson N, Mahil SK, Hassi NK, Wohnhaas CT; APRICOT and PLUM study team, Burden AD, Griffiths CE, Ingram JR, Levell NJ, Parslew R, Pink AE, Reynolds NJ, Warren RB, Visvanathan S, Baum P, Barker JN, Smith CH, Capon F. Single-cell analysis implicates Th17 to Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis. J Allergy Clin Immunol. 2022 May 11: S0091-6749(22)00624-8

• Cro S, Cornelius VR, Pink AE, Wilson R, Pushpa-Rajah A, Patel P, Abdul-Wahab A, August S, Azad J, Becher G, Chapman A, Dunnil G, Ferguson AD, Fogo A, Ghaffar SA, Ingram JR, Kavakleiva S, Ladoyanni E, Leman JA, Macbeth AE, Makrygeoegou A, Parslew R, Ryan AJ, Sharma A, Shipman AR, Sinclair C, Wachsmuth R, Woolf RT, Wright A, McAteer H, Barker JNWN, Burden AD, Griffiths CEM, Reynolds NJ, Warren RB, Lachmann HJ, Capon F, Smith CH. Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two staged, adaptive placebo controlled trial (APRICOT). Br J Dermatol, 2022 186: 245-256