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  • Project No: NDORMS-2021/2
  • Intake: 2021

PROJECT OUTLINE

Cellular stress has been implicated in many inflammatory processes including the pathogenesis of Ankylosing Spondylitis and related Spondyloarthritides. Serine/threonine-protein kinase/endoribonuclease (IRE1) senses ER stress and activates X-box binding protein 1 (XBP1) through cytosolic mRNA splicing and the generation of spliced XBP-1 (XBP1s). The IRE1/XBP1 pathway has been shown to induce the immune response acting either within macrophages, T cells and NK cells or through crosstalk of different immune cells. [1-3]

The IRE1/XBP1 pathway has previous been shown to support Th17 cell differentiation from murine naïve CD4+ T cells. [2] We have generated data supporting similar mechanisms in human CD4+ Th17 cells (un-published data). In this DPhil project, you will study if IRE1/XBP1 pathway is required for the function of two major IL-17-producing innate like lymphocytes (γδ T cells and mucosal associated invariant T (MAIT) cells). The molecular mechanism and therapeutic potentials of targeting IRE1/XBP1 pathway will also be investigated. The later will be tested in the context of Ankylosing Spondylitis (AS), a form of inflammatory arthritis featured by the enhanced Th17 responses in both conventional T cells and innate like lymphocytes.

With training and support from CHEN and BOWNESS groups, you will undertake a T cell immunology-based project with the aim to unravel novel molecular mechanism and translational applications of regulating Th17 response through modulating IRE1/XBP1 pathways.

Research aims and plans

To achieve the overall goal of investigating functional roles of IRE1/XBP1 pathway in Th17 response in human T cells, the following specific aims will be addressed.

Aim-1: Confirming the regulatory role of IRE1/XBP1 in Th17 response in human CD4, γδ T cells and MAIT cells

You will investigate the functional role of the IRE1/XBP1 pathway in Th17 immune response studying conventional and innate like lymphocytes from healthy donors and patients with AS, using genetic knockdown and chemical inhibitors. Th17 cytokines, such as IL-17A, IL-17F and GM-CSF, will be used as the readout (measured by ELISA and flow cytometry).

Aim-2: Investigating the molecular mechanisms underlying the regulation of Th17 response by IRE1/XBP1

RNA-seq (bulk and single cell) in combination with gene knockdown/knockout will be utilized to interrogate the downstream pathways regulated by IRE1/XBP1. ChIP-seq will be used to identify the genomic regions that XBP1 binds to and regulate. Further gene knockdown/knockout will be performed to confirm the functional relevance of findings from RNA-seq and ChIP-seq with Th17 response.

Aim-3: Exploring the translational potentials of targeting IRE1/XBP1 pathway to treat Ankylosing Spondylitis

You will look for the evidence of IRE1/XBP1 activation in ankylosing spondylitis (AS) using the single cell RNA-seq and CyTOF datasets from AS patient blood and joints (un-published data from Bowness lab). If the IRE1/XBP1 inhibitor suppresses Th17 response from patients with AS, there would be the opportunity for in vivo translational investigation using a murine model for AS (SKG) in collaboration with colleagues at the Kennedy Institute for Rheumatology (also within NDORMS). 

TRAINING

You will receive training in following aspects: 1) human primary T cell culture/expansion, 2) designing and performing inflammation-relevant cellular assays using primary T-cells (techniques including ELISA, flowcytometry, qPCR and western blot), 3) gene knockdown and overexpression in primary T-cells (techniques including standard molecular biology techniques, in-vitro mRNA translation and lentivirus production for gene knockdown and overexpression), 4) bulk and single cell RNA-seq, ChIP-seq for mechanistic study, 5) designing cellular assays to model inflammation-driven disease for translational investigation, 6) opportunity to work with sing cell RNA-seq and CyTOF data of blood and joint tissue samples.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome.

Students will also be required to attend regular seminars within the Department and those relevant in the wider University. Students will be expected to present data regularly in Departmental seminars, lab meeting within Chen and Bowness groups and to attend external conferences to present their research globally, with limited financial support from the Department.

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

HOW TO APPLY

The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Graduate Studies Officer, Sam Burnell (Samuel.burnell@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements. Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2021.

 Applications should be made to one of the following programmes using the specified course code:

D.Phil in Musculoskeletal Sciences (course code: RD_ML2)

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

REFERENCES

 1.         Martinon, F., et al., TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol, 2010. 11(5): p. 411-8.

2.         Brucklacher-Waldert, V., et al., Cellular Stress in the Context of an Inflammatory Environment Supports TGF-beta-Independent T Helper-17 Differentiation. Cell Rep, 2017. 19(11): p. 2357-2370.

3.         Dong, H., et al., The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. Nat Immunol, 2019. 20(7): p. 865-878.

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