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  • Project No: #OxKEN-2021/15
  • Intake: OxKEN

PROJECT OVERVIEW

Lysosomes are the essential recycling machinery of the cell, receiving and degrading biological macromolecules, and liberating their components for reuse.

They are also multifunctional signalling platforms, with critical roles in sensing cellular nutrient status, controlling apoptosis, and in immunity against microbes, including HIV, SARS-CoV2, and cholera.

Shortly after their identification in the late 1960s, it was noted that lysosomes accumulate in the immune cells of patients with the often severe and not infrequently fatal autoimmune disease systemic lupus erythematosus (SLE). However, why this happens and what the consequences are for autoimmunity remains essentially unknown. This is important, because SLE has great unmet treatment needs, with limited and often ineffective options.

We’ve recently shown that autophagy, a fundamental process for transferring intracellular cargo to the lysosome, is defective in SLE, and that genetic variants in lysosome signalling adapters can predispose to the disease. We’ve also found that lysosomal function can be modulated, with important effects on the immune system.

In this project, you will examine the hypothesis that a build-up of self-nucleic acids and antigens in a defective lysosomal system triggers an immune response which drives SLE. Lysosomes are vital to terminate signalling by toll like receptors (TLRs) in endosomes, which recognise self-nucleic acids. This may also contribute to the inflammatory state seen in aging, again associated with lysosomal defects.

Our aim is to translate lysosomal modification into novel treatment approaches for SLE and other autoimmune diseases.

To do so, you will start work with human patients, using a full spectrum of advanced techniques to image lysosomes and analyse their function in immune cells. Following on will be detailed mechanistic study, using experimental models of autoimmune disease and lysosomal dysfunction. Finally restoration of lysosomal function using genetic and pharmacologic approaches will be tested in disease models to provide a foundation for clinical use.

 KEYWORDS

Lysosome

SLE

Autoimmunity

Autophagy

Innate immunity

TRAINING OPPORTUNITIES

This project will provide comprehensive coverage of standard and advanced human and experimental immunology techniques, including flow cytometry, confocal imaging, in vitro cell culture, and quantification of lysosomal function. The student will have the opportunity for patient contact to collect samples, and develop clinical research skills. There will be opportunities to acquire skills in bioinformatic analysis of large data sets generated by genomic techniques during the project. The student will develop detailed understanding of genetically modified models of cellular function and disease, and their role in developing mechanistic and therapeutic insights.

KEY PUBLICATIONS

  1. Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol Feb;21(2):101-118 (2020)
  2. Clarke, A. J. et al. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann Rheum Dis 74, 912–920 (2015).
  3. Bonam, S. R., Wang, F. & Muller, S. Lysosomes as a therapeutic target. Nat Rev Drug Discov 1–26 (2019).
  4. Clarke, A. J. & Simon, A. K. Autophagy in the renewal, differentiation and homeostasis of immune cells. Nat Rev Immunol 1–14 (2019).
  5. Zhang H et al. Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence. Mol Cell Oct 3;76(1):110-125 (2019)

CONTACT INFORMATION OF ALL SUPERVISORS

Katja Simon

Alexander Clarke