Ubiquitin signalling regulation and inhibition in autoimmune disease

During the PhD, I will study deubiquitylase (DUB) enzymes and first-in-class DUB inhibitors that reduce inflammatory receptor signalling by building on a negative feedback mechanism in cells.

DUB targeting of the IFNAR1 receptor can selectively cleave lysine 63-linked ubiquitin chains, promoting downstream JAK/STAT signalling, leading to increased expression of interferon stimulated genes (ISGs). Activation of the type I Interferon (IFN) pathway plays a key role in the pathogenesis and progression of several autoimmune diseases including Systemic Sclerosis (SSc) and Systemic Lupus Erythematosus (SLE).

Whilst Type I IFN inhibition using monoclonal antibodies against the IFN receptor is an approved therapy for SLE and is currently being tested in SSc, neutering IFN signalling has adverse effects due to reduced response to viral infections and cellular damage signals. The multifactorial nature of immune signals warrants the discovery of alternate strategies to target the aberrant signalling presented by multiple immune receptors.

Several DUB inhibitors and molecular glues have been identified as promising tools and potential therapeutics and this project will provide the initial stepping stone for future industry collaboration to explore the biological activity of BRISC inhibitors in preclinical models of disease, informing the next generation of innate immune activity therapeutics.

The main objectives of this project are to:

Identify the biological effects of DUB inhibitors and molecular glues in immune signalling using cellular disease models. Understand how DUBs and their interactors regulate receptor degradation via the ubiquitin system. The Skills and Techniques that will be developed over this project include: Enzyme assays and in vitro enzyme inhibition studies

Cell biology and cellular inhibition studies Flow cytometry / fluorescence-activated cell sorting (FACS) Gene expression arrays and RNAseq analysis Mass spectrometry / whole cell and quantitative proteomics Communication skills and working with teams across disciplines Scientific writing and data analysis skills