Background
The involvement of proinflammatory cytokine IL17 has been linked to multiple chronic inflammatory diseases which has impaired wound healing and fibrosis development. The increase in IL17 level has been identified in a wide range of chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), Primary Biliary Cholangitis (PBC), and Sclerosing Cholangitis (PSC). Chronic liver disease is estimated to affect 800 million people worldwide with no effective anti-fibrotic treatments.
It is well known that IL17 promotes fibrogenesis through the activation of fibroblasts. However, the role of IL17 on epithelial cell fate and regeneration is less clear, especially with recent work suggesting that IL17 signalling prime epithelial proliferation in response to injury1, which fits with our preliminary data in our lab showing that IL17 signalling primes liver stem cell activation. We have shown previously that cholangiocytes in the liver become regenerative liver stem cells in response to injury but the exact mechanisms which control this remains to be investigated2. Furthermore, the emergence of the regenerative cholangiocytes tends to correlate with scar deposition around the regenerative niche which has a mixture of proliferating epithelial cells, immune cells, fibroblasts, and scar deposition. It is unclear whether the emergence of IL17a cells and signalling in the liver is a protective mechanism or an indicator of poor prognosis in human diseases. Although pan- blockade of IL17 treatment such as Secukinumab has been on Phase 1/2 clinical trials for psoriasis, however, with the wide spectrum of chronic liver diseases and pathology, we wonder whether “one treatment fits all”?
Here, we aim to analyse published, publicly available single cell RNA (scRNA) sequencing datasets across a spectrum of liver diseases with variable aetiology such as cirrhosis, NAFLD, PSC and analyse whether IL17 and its implications on the regenerative cholangiocytes2,3. This will stratify the role of IL17 and cholangiocytes across a spectrum of liver diseases and characterise the cholangiocytes in different diseases transcriptionally, answering whether IL17 make regenerative cholangiocytes pathogenic?
To complement the findings from scRNA sequencing datasets from clinical samples, we will use a mouse model which IL17 receptor is conditionally deleted in the cholangiocytes (Krt19CreERT2tdTomatoloxSTOPloxIL17Raflox) to inhibit IL17 signalling on cholangiocytes. Models of biliary or hepatocyte damage will be used on the transgenic mice in the presence or absence of cholangiocyte IL17 signalling. scRNA sequencing will be performed to investigate whether the absence of IL17 signalling on cholangiocytes alters the immune and regenerative landscape in the liver. Furthermore, this dataset will be used to match with the human datasets available publicly to identify matching cholangiocytes populations in human diseases. Qualitative & quantitative proteomics analysis will be performed on isolated murine cholangiocytes to identify pathogenic vs regenerative protein signatures (Proteomics and Metabolomics Facility, Roslin Institute).
The cholangiocytes specific IL17 inhibition strategy will show whether IL17 signalling differs in response to different injury mechanisms (i.e biliary vs hepatic), stratifying IL17 targeting treatment based on disease aetiology and complementing the pan-IL17 blockade strategies.
Dissecting the cell specific effect of IL17 on tissue regeneration and fibrosis, we aim to work towards the overarching aim to understand the role of IL17 signalling in chronic liver diseases - a friend or foe? More importantly, leading to targeted treatments for chronic liver disease based on disease aetiology.
Aims
1) Analyse publicly available clinical datasets to identify IL17 signalling and its downstream targets on the liver epithelium.
2) Use murine models to investigate the role of IL17 on the fate of cholangiocytes and match its relevance to human diseases.
3) Combining transcriptomic and proteomic analysis to identify pro-regenerative signatures of cholangiocytes which leads to a more targeted therapeutic approach.
Training outcomes
1)Training in cutting-edge computational approaches to analyse next-generation sequencing data (Bulk and scRNA sequencing). Packages include CellphoneDB, Slingshot.
2) Designing, perform, and analyse data obtained from in vivo mouse models. Detailed phenotyping of models using multiparameter flow cytometry, histology and multiplex imaging platform, with potential to explore spatial transcriptomics.
3) 3D in vitro culturing system (organoid + co-culture), using cells from both murine and human (explants/ livers deemed unsuitable for clinical transplantation).
Q&A Session
If you have any questions regarding this project, you are invited to attend a Q&A session hosted by the Supervisor(s) on 7th December at 11am via Microsoft Teams. Click here to join the meeting.
About the Programme
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.
Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the following link:
https://www.ed.ac.uk/usher/precision-medicine/app-process-eligibility-criteria
For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine
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