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.
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.