Functional investigation of inflammatory intestinal disease susceptibility genes
Lead Research Organisation:
Queen Mary University of London
Department Name: Blizard Institute of Cell and Molecular
Abstract
Recent advances in human genetics (Human Genome Project, HapMap Project, technology) now enable us to study most of the common genetic variation that makes us different from one another. By comparing people with and without disease in a genome wide association study, genes can be pinpointed that predispose to common intestinal inflammatory diseases (coeliac disease, Crohn‘s disease, ulcerative colitis). A recent success has been the identification of genetic variants in IL23R (a protein involved in inflammation) and the confirmation of NOD2 as genes predisposing to Crohn‘s disease. The challenge is then to understand how genetic variation leads to changes in biology. We have previously done this for NOD2 in Crohn‘s disease. We have preliminary data using human samples on how we might show that IL23R genetic variation has an effect on immune system function, and the development of Crohn‘s disease and other autoimmune diseases. Initially the project will study IL23R, later ATG16L1, then possibly a further gene arising from the genome wide association studies. Studying the biology of how genetic variants influence inflammatory diseases will have implications for novel therapeutics and diagnostics for these diseases, leading to better treatments.
Technical Summary
Aims
Advances in human genetics now enable for the first time identification of primary genetic variants predisposing to common inflammatory intestinal diseases (coeliac disease, Crohn‘s disease and ulcerative colitis). Early successes include NOD2, IBD5/5q31 and IL23R variants predisposing to Crohn‘s disease. However only for NOD2 have we begun to understood how genetic variation might influence biological function and cause intestinal inflammation. Genome wide association studies are currently in progress in coeliac disease (our group) and Crohn‘s disease/ulcerative colitis (at least three groups worldwide). These will shortly uncover many further disease predisposing genetic variants. The sim is to understand how these influence biological function.
Objectives
Convincingly replicated genetic variants from the current genome wide studies in intestinal inflammatory diseases will be identified. A range of techniques will be used to understand how genetic variation influences biological function, and might lead to intestinal inflammation. We have previously performed such studies for NOD2, and have preliminary data for IL23R. It is proposed the Fellow will initially investigate IL23R, later ATG16L1, and possibly a further disease gene arising from the genome wide association studies.
Design
Studies will be primarily performed using human samples, from healthy controls and from patients with intestinal disease. Although animal models exist, these often poorly reflect human intestinal biology. Human samples will include cell lines, fresh peripheral blood, histological archive intestinal tissue, and fresh surgical small/large intestinal specimens. Precise studies will depend on the biological function of the gene containing disease associated genetic variation. In general, we will first understand the normal function of the gene (extensive literature search, if necessary descriptive experiments). Second an assay for gene function will be developed and compared in disease versus health, and sub-stratified by genetic variation. The key endpoint will be how different genotypes at a locus influence biological function.
Methodology
Descriptive (e.g. gene expression at mRNA, protein level in tissue/cell samples; bioinformatics). Quantitative (e.g. for NOD2 muramyl dipeptide induced peripheral blood IL-8 response; for IL23R activated peripheral blood / lamina propria T cell cytokine dose response to IL23). Comparison between disease and controls, substratified by genotype. We have published using this methodology for NOD2, and have are developing assays for IL23R.
Scientific and Medical Opportunities
Detailed understanding of how disease associated genetic variants alter biological function will provide insight into primary causes of disease. This will enable targeted development of novel therapeutic strategies, and better treatments for patients.
Advances in human genetics now enable for the first time identification of primary genetic variants predisposing to common inflammatory intestinal diseases (coeliac disease, Crohn‘s disease and ulcerative colitis). Early successes include NOD2, IBD5/5q31 and IL23R variants predisposing to Crohn‘s disease. However only for NOD2 have we begun to understood how genetic variation might influence biological function and cause intestinal inflammation. Genome wide association studies are currently in progress in coeliac disease (our group) and Crohn‘s disease/ulcerative colitis (at least three groups worldwide). These will shortly uncover many further disease predisposing genetic variants. The sim is to understand how these influence biological function.
Objectives
Convincingly replicated genetic variants from the current genome wide studies in intestinal inflammatory diseases will be identified. A range of techniques will be used to understand how genetic variation influences biological function, and might lead to intestinal inflammation. We have previously performed such studies for NOD2, and have preliminary data for IL23R. It is proposed the Fellow will initially investigate IL23R, later ATG16L1, and possibly a further disease gene arising from the genome wide association studies.
Design
Studies will be primarily performed using human samples, from healthy controls and from patients with intestinal disease. Although animal models exist, these often poorly reflect human intestinal biology. Human samples will include cell lines, fresh peripheral blood, histological archive intestinal tissue, and fresh surgical small/large intestinal specimens. Precise studies will depend on the biological function of the gene containing disease associated genetic variation. In general, we will first understand the normal function of the gene (extensive literature search, if necessary descriptive experiments). Second an assay for gene function will be developed and compared in disease versus health, and sub-stratified by genetic variation. The key endpoint will be how different genotypes at a locus influence biological function.
Methodology
Descriptive (e.g. gene expression at mRNA, protein level in tissue/cell samples; bioinformatics). Quantitative (e.g. for NOD2 muramyl dipeptide induced peripheral blood IL-8 response; for IL23R activated peripheral blood / lamina propria T cell cytokine dose response to IL23). Comparison between disease and controls, substratified by genotype. We have published using this methodology for NOD2, and have are developing assays for IL23R.
Scientific and Medical Opportunities
Detailed understanding of how disease associated genetic variants alter biological function will provide insight into primary causes of disease. This will enable targeted development of novel therapeutic strategies, and better treatments for patients.