Identifying Inflammatory Bowel Disease Pathotypes

Basic & Clinical Research
Keywords:Inflammatory bowel disease, disease stratification
Inflammatory bowel disease (IBD) has become increasingly common in recent years and currently affects 1 in 200 people in the UK. It's associated with considerable suffering & loss of quality of life and costs the NHS over £1 billion a year.IBD is an umbrella term for a range of diseases.The two main subtypes are Crohn's Disease (CD) and Ulcerative Colitis (UC), which vary with respect to the part of the intestine that is affected and other disease characteristics.However, IBD in some people cannot be classified as UC or CD-they are said to have an 'indeterminate' IBD (iIBD) subtype.In fact, it is now becoming clear that there is substantial diversity of disease between patients within the CD, UC and iIBD subtypes and importantly, this can profoundly affect responses to treatment. Currently, patients typically follow a 'step-up' therapy model in which immunosuppressant drugs of increasing strength are administered until a positive response is achieved.The most powerful, but most expensive, drugs are called 'biologics'-they target specific molecules that can cause chronic inflammation.All treatments are associated with side effects.Clearly, it would be enormously beneficial if, at the start of treatment, it were possible to determine which drug would work best in each patient.This would reduce suffering, limit unnecessary side effects, and reduce the financial burden on the NHS.In this PhD project we will undertake a detailed examination of blood and tissue from IBD patients and healthy people with the aim of identifying new IBD subtypes.We refer to these subtypes as 'immunopathotypes'.This will be done as part of an ongoing collaboration with gastroenterologists based at Glasgow's Royal Infirmary.They will provide a constant source of blood and tissue biopsies from the intestine for our analysis.We will measure levels of inflammatory proteins in the blood and characterise white blood cells using flow cytometry, an approach that identifies cells using combinations of fluorescently labelled antibodies.The fragments of intestinal tissue will be analysed using a technique called RNAseq - this allows us to determine which of the many thousands of human genes are active in the intestines of patients with IBD compared to healthy people. These methods will allow us to generate large amounts of data from each person in a very short period of time. We will be able to compare data from the same type of sample taken from different people, and look for links between tissue biopsies and blood samples taken from the same patient. We will also be able to explore if there are any clear links between our data and the patients' clinical information.These analyses will be challenging and require an in depth understanding of statistics and computing, which in the context of biological data are referred to as 'bioinformatics'. These approaches will allow us to categorise ('stratify') patients more comprehensively and rationally, and hopefully improve our understanding of the variation in disease in patients with IBD.Ultimately it could help improve the treatment of these patients.This project will develop a variety of key scientific and interpersonal skills.First, expertise will be established in a variety of fundamental lab techniques that are used widely in basic and clinical research.Second, the work will build a detailed understanding of how to apply bioinformatics to the analysis of large datasets.Bioinformatics is becoming increasingly important in modern science so developing expertise in this area could have long-term career benefits.Third, given the nature of the work, the project requires a detailed understanding of ethical issues surrounding the use human material and the ways that ethical approval is secured for such studies.Close cooperation with the clinic means it's essential to learn how to interact with doctors, nurses, patients & their families