The SPICeD project - Spatial transcriptomics to understand Parenchymal-Immune interactions in Coeliac Disease

Theme Overview

The SPICeD project (Spatial transcriptomics to understand Parenchymal-Immune interactions in CoeliacDisease) is a DPhil project to discover and understand cell-cell interactions in the intestinal mucosa in coeliac disease, and their significance in the disease pathology. This project will involve training and exposure in both wet-lab and bioinformatics approaches in the field of spatial biology. Full home funding and stipend is available for a 3-year DPhil starting in autumn 2023. A full application needs to be made before 23rd June 2023 to the DPhil in Clinical Medicine programme (including references) - DPhil in Clinical Medicine.

Coeliac disease disease is an immune-mediated disorder triggered by gluten in the diet that affects 1-2% of the population. There is no cure, and no treatment other than a lifelong, strict gluten-free diet. Sometimes inflammation in the gut continues despite removal of gluten (refractory coeliac disease - RCD), which can develop into a rare type of lymphoma. The immunology of the condition remains incompletely understood, and there remains a considerable unmet need for novel diagnostics, monitoring and therapeutics.  

Our recent work has used single-cell RNA sequencing (scRNAseq) to examine immune and epithelial cells in the gut in coeliac disease. This work revealed striking changes in specific subtypes of CD4+ and CD8+ T cells, epithelial progenitors, and enteroendocrine cells, as well as other parenchymal cell populations. These changes are restricted to the small bowel mucosa, and so to further understand coeliac immunology we must understand immune-parenchymal interactions in the gut itself, including their spatial position in the gut mucosa.  

We hypothesise that the complex inflammatory pathology of CD comprises a set of functional ‘units’ of immune and parenchymal cell types interacting in specific ways, physically co-located in the gut mucosa.

Spatial transcriptomics is a rapidly expanding novel field where next-generation sequencing platforms are leveraged to understand how gene expression changes not only at the single-cell level, but within the microstructure of tissues. This research, when coupled with single-cell RNA sequencing analyses, can provide understanding about cell-cell interactions and signalling pathways driving disease within tissue. Recent advances in spatial transcriptomic technology can provide sub-cellular resolution, enabling interrogation of complex spatial structures such as the intestinal crypt villous axis, mucosal immune follicles, and complex immune-parenchymal cell interactions as seen in autoimmune and inflammatory conditions like CD. 

This project will test this hypothesis through study of the spatial arrangement of immune cell types in the gut in CD, and the cell-cell interactions between intestinal immune and parenchymal cells. We will apply novel spatial transcriptomic approaches, along with multiplex immunohistochemistry tissue staining, to understand the spatial biology in the intestine in active and treated CD, the dynamic state of a gluten challenge, as well as refractory coeliac disease. This will provide insights into pathways that drive disease, informing our understanding of triggers and biology of CD, and potential treatments.

 This project involves training and experience in wet-lab techniques, next-generation sequencing, and bioinformatic analyses, and so is particularly suited to an applicant looking to develop a bioinformatic specialist interest. The project will be co-supervised by a team with immunological, clinical coeliac disease, and spatial bioinformatics expertise. 

If you would like to discuss the project and training opportunities in more detail, please directly contact Michael FitzPatrick ([Email Address Removed]).

Training Opportunities

T cell immunology, FACS sorting, human tissue processing, single-cell sequencing, spatial transcriptomics, and functional assays. There will also be extensive training and supervision in bioinformatic analysis approaches for single-cell sequencing and spatial transcriptomics.