Using single-cell RNA sequencing to elucidate the biological basis of IBD and response to therapy
type: CreativeWork
description: Inflammatory bowel disease (IBD) is an umbrella term for disorders involving chronic inflammation of the gastrointestinal tract, with over 6 million cases reported worldwide. 320 IBD risk loci have been identified for this disease, however, the role of many of these risk loci in the pathogenesis of IBD is largely unknown. While there is no cure for IBD, biologic treatments including anti-TNF have improved the quality of life for many IBD patients. Unfortunately, many patients will fail to respond or lose response to anti-TNF treatment over time. In this thesis, single-cell RNA sequencing (scRNA-seq) was utilised to understand the biological basis of IBD and response to anti-TNF therapy. The first project utilised peripheral blood mononuclear cells (PBMCs) to investigate the effects of IBD-associated genetic variants in an ex vivo setting, while the second project utilised a co-culture model to understand the immune-cell response to anti-TNF therapy. In the first research chapter of this thesis, scRNA-seq was performed on resting PBMCs from healthy donors recruited with carriage of risk variants in the adenylate cyclase (ADCY) genes ADCY3 and ADCY7, to understand the role of these IBD risk variants in immune cells. A trans-eQTL analysis performed in the immune cells of donors with carriage of the rare coding ADCY7 variant rs78534766 identified 65 unique trans-genes and enriched pathways related to cytokine signalling and the citric acid cycle. Colocalisation analysis using updated CD genome-wide association summary statistics from our lab showed that the disease-associated variant likely decreased the expression of ADCY3 in immune cell subsets including CD4+ T cells. Only a single trans-eQTL effect was detected for the ADCY3 CD-associated variant, suggesting the study was not appropriately powered to detect trans effects of modest effect regulatory variants. The second and third research chapters utilise a co-culture model of CD4+ memory T cells and macrophages to in…
abstract: Inflammatory bowel disease (IBD) is an umbrella term for disorders involving chronic inflammation of the gastrointestinal tract, with over 6 million cases reported worldwide. 320 IBD risk loci have been identified for this disease, however, the role of many of these risk loci in the pathogenesis of IBD is largely unknown. While there is no cure for IBD, biologic treatments including anti-TNF have improved the quality of life for many IBD patients. Unfortunately, many patients will fail to respond or lose response to anti-TNF treatment over time. In this thesis, single-cell RNA sequencing (scRNA-seq) was utilised to understand the biological basis of IBD and response to anti-TNF therapy. The first project utilised peripheral blood mononuclear cells (PBMCs) to investigate the effects of IBD-associated genetic variants in an ex vivo setting, while the second project utilised a co-culture model to understand the immune-cell response to anti-TNF therapy. In the first research chapter of this thesis, scRNA-seq was performed on resting PBMCs from healthy donors recruited with carriage of risk variants in the adenylate cyclase (ADCY) genes ADCY3 and ADCY7, to understand the role of these IBD risk variants in immune cells. A trans-eQTL analysis performed in the immune cells of donors with carriage of the rare coding ADCY7 variant rs78534766 identified 65 unique trans-genes and enriched pathways related to cytokine signalling and the citric acid cycle. Colocalisation analysis using updated CD genome-wide association summary statistics from our lab showed that the disease-associated variant likely decreased the expression of ADCY3 in immune cell subsets including CD4+ T cells. Only a single trans-eQTL effect was detected for the ADCY3 CD-associated variant, suggesting the study was not appropriately powered to detect trans effects of modest effect regulatory variants. The second and third research chapters utilise a co-culture model of CD4+ memory T cells and macrophages to in…
author: Banks, Harriet
language: eng
keywords: ADCY3, ADCY7, adenylate cyclase, anti-TNF therapy, co-culture, Crohn's disease, IBD, IBD risk loci, inflammatory bowel disease, macrophages, scRNA-seq, single-cell RNA sequencing, T cells, TNF, tumour necrosis factor, ulcerative colitis, infliximab
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9e3cee8b-e6e8-4724-91ba-41d9bcf93885/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2024-05-31
date modified: 2026-07-22T22:24:10Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.116045