Discovering novel immunoregulatory molecules underlying the pathogenesis of systemic lupus erythematosus

This project is suitable for an Honours, Masters or PhD student.

BACKGROUND

Many important metabolites that signal via purinergic receptors (molecules in the plasma membrane) are obtained from food or synthesized by the body. BAFF is a B cell survival factor, and the overexpression of BAFF in BAFF-transgenic (BAFF-Tg) mice causes the expansion of autoreactive pathogenic B cells leading to systemic lupus erythematosus (SLE). Research has shown that BAFF-Tg mice are deficient in a range of these metabolites.

We have demonstrated that BAFF-Tg mice fed a high-fibre diet express a high level of a particular metabolite, which is associated with a reduction in autoreactive B cell numbers and protection from SLE. Supplementation also protects the BAFF-Tg mice against SLE. However, the cellular and molecular mechanism by which the metabolite protects against SLE is not known. We have generated mice deficient in the purinergic receptor (PR) associated with the metabolite for use in this project.

AIMS

The aims of this project are to:

• Investigate the requirement of a purinergic receptor in the high-fibre diet-mediated protection against SLE.
• Investigate if metabolite- purinergic receptor signalling is critical for the protection against SLE.
• Characterise a novel metabolite therapy for SLE.

This project will use a range of immunological techniques (mouse models of experimental SLE, flow cytometry, confocal microscopy, ELISA), metagenomic sequencing, microbiome analysis and metabolomics to characterise the immunological mechanisms of action. We will validate the research findings using clinical samples.

PROJECT POTENTIAL

To develop an entirely new treatment avenue for lupus and explore a novel set of metabolites and signalling pathways with significant clinical potential.