Project ID iCASE2023_04

ThemeCM-HD

Co Supervisor 1A Faculty of Life Sciences and MedicineSt John’s Institute of DermatologyWebsite

Co Supervisor 1B Faculty of Life Sciences and MedicineDepartment of Medical and Molecular GeneticsWebsite

Partner AstraZeneca

Dissecting shared mechanisms of response to targeted therapies for eczema: a single-cell approach

Partner: AstraZeneca

Eczema is a common and debilitating long-term skin disease caused by changes in the immune system. Recently, research has delivered new drugs for eczema including dupilumab (a biologic) and JAK inhibitor treatments. However, 6 in 10 people who take dupilumab or JAK inhibitors do not get better. Side effects are unpredictable, for example 1 in 2 people taking dupilumab experience new or worse eye problems. Not knowing which treatments will work is expensive (drug costs are ~£10,000 per year per patient) and places patients at risk of continued poorly controlled eczema and drug side-effects. The BEACON clinical trial (starting Q1 2023) is the first study in the world to address this problem by directly comparing eczema drugs. BEACON presents an ideal platform to understand how different drugs resolve eczema, so we can use them more efficiently.

This project will use a multi-layered approach to characterise the immune cell populations and mechanisms that drive the effects of newly identified eczema drugs. Specifically, the student will:

  1. Identify the cells, cell-cell interactions and gene regulatory networks that coordinate early treatment effects by analysing skin biopsies from BEACON participants using single-nuclear RNA sequencing.
  2. Define the spatial context of the cell subpopulations underpinning treatment actions in skin using RNA in situ hybridisation.
  3. Investigate whether the activation of these cells can be monitored in blood using immune profiling of matched blood samples from the BEACON cohort.

This project offers comprehensive training in wet-lab and computational approaches in skin biology and single-cell methods. By comparing drug actions, the student will build a complete picture of how cells work together to resolve eczema. This will help us understand why certain drugs work in certain people, so we can ensure the right patient receives the right drug first-time and design better treatments for the future.

The student will join a supportive, high performing multi-disciplinary research group at St John’s Institute of Dermatology, a world-leading centre of excellence in skin research. The student will have a basic science and a clinical academic supervisor with combined expertise spanning inflammatory skin diseases, genetics, transcriptomics research and computational data analysis. Both supervisors have a track record of working closely together to produce high impact outputs. They will spend at least 6 months during year 3 with our industry partner AstraZeneca, where they will be embedded within the Asthma and Skin Immunity Bioscience Team, Cambridge, UK and pursue lab-based activities for Aim 2 of the project.

The student will undertake a structured training programme to equip them with both analytical and experimental research skills. While previous experience in computational data analysis is desirable, training in R programming will be provided if needed. The applicant should be highly motivated, striving for research and training excellence, and an effective interdisciplinary communicator.

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 CEM, 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 Oct;150(4):882-893. doi: 10.1016/j.jaci.2022.04.027. Epub 2022 May 12. PMID: 35568077.

Mahil SK, Bechman K, Raharja A, Domingo-Vila C, Baudry D, Brown MA, Cope AP, Dasandi T, Graham C, Lechmere T, Malim MH, Meynell F, Pollock E, Seow J, Sychowska K, Barker JN, Norton S, Galloway JB, Doores KJ, Tree TIM, Smith CH; The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study. The Lancet Rheumatology 2021;39:467-78.