Building human intestinal organoid-based models to study pathological matrix remodelling in Inflammatory Bowel Disease

Overview

Inflammatory bowel disease (IBD) can impact the matrix surrounding the gut epithelium, causing fibrosis and fistulae; however, it is unknown whether mechanical changes to the gut matrix are a cause or consequence of inflammation. This project will use human intestinal organoid (HIO)-based models of IBD to understand how the mechanical properties of the matrix contribute to IBD-like phenotypes in the epithelium. Through this, we aim to reveal novel matrix-modulating targets that can be exploited therapeutically to treat IBD. 

Project details

Cells and tissues are known to respond to mechanical cues during development, tissue maintenance and in disease. However, cells are not merely passive sensors of physical signals, but rather actively modify their local environment via both extracellular matrix (ECM) production and degradation (Blache, Nat Biomed Eng, 2020). We have previously used HIO encapsulated within synthetic hydrogels to identify a novel role for a rare immune cell type (type I innate lymphoid cells) in regulating gut matrix remodelling (Jowett, Nat Mater, 2021). In this project, we aim to build on our previous work to study how pathological matrix remodelling impacts the intestinal epithelium, and how inflammatory phenotypes in the epithelium impact the gut matrix.

HIO are a well-established, accessible model of the intestine, containing both epithelial and mesenchymal cells. Here we will use HIO and modifiable PEG-based synthetic hydrogels to create ‘IBD-in-a-dish’ models. We will: 

• Identify a combination of synthetic hydrogel stiffness, degradability, and adhesive ligand concentrations that in combination with appropriate exogenous cytokines lead to encapsulated HIO taking on IBD-like phenotypic characteristics (IBD-in-a-dish).
• Map the extent to which HIO mechanically modify their local environment using atomic force microscopy. We will also encapsulate HIO in hydrogels that soften or stiffen, mimicking pathological stiffening (fibrosis) or degradation (fistulae), to determine if mechanical changes are sufficient to prompt inflammatory phenotypes.
• Determine whether specific secreted proteins mediate HIO’s ability to respond to mechanical modifications using targeted RNAi against specific secreted proteins or tethering of specific proteins to the hydrogel.
• Apply RNAsequencing and SILAC-based proteomics to the HIO-synthetic hydrogel-based IBD model to validate known matrix components that are regulated in IBD and identify novel targets that could be exploited therapeutically to treat IBD.

Person specification

We are looking for a motivated, ambitious student to join or multi-disciplinary research team. We are recruiting a student with a BSc/MSc in cell biology, molecular biology, biomedical sciences or a related subject area (2:1 minimum), who also has an interest in the physical sciences. Experience with biomaterials and/or mammalian cell culture, preferably with iPSC or organoids, is a plus.

Research training

The appointed student will be trained in culturing human induced pluripotent stem cells and their differentiation into intestinal organoids. They will also be taught chemical synthesis to create hydrogel components and techniques to analyse chemical modifications, including by NMR, HPLC and SEC. They will also develop skills in gene expression analyses, atomic force microscopy force spectroscopy, and confocal microscopy. The student will also generate samples for RNA sequencing and proteomics analyses and will work with core facilities and bioinformaticians to analyse -omics data.

To view entry requirements and further general information, see Dental and Health Sciences Research MPhil/PhD prospectus page.

Next steps

Please apply online at apply.kcl.ac.uk following these steps:

1. Register a new account/login.
2. Once logged in, select Create a new application.
3. Enter ‘Dental and Health Sciences Research MPhil/PhD (Full-time)/(Part-time)' under Choose a programme. Please ensure you select the correct mode of study.
4. Select Ocober 2021 as the start date.
5. Please note: Applicants must include the project reference number (2021/DOCS/03) in the 'Research proposal' and 'Funding (point 5)' sections of the application.

Applications must be received by the deadline specified in this listing.

Applicants are strongly encouraged to discuss projects with the first supervisor prior to submitting an application.