Identification and characterisation of causal molecules for Crohn's disease and ulcerative colitis

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Summary Crohn's disease (CD) and ulcerative colitis (UC) are the two major inflammatory bowel diseases. Both conditions occur in about 1 in 1000 of the population and have a major impact on those affected. Up to 75% of CD and 25% of UC patients will require surgery at least once, and both conditions are associated with a significantly increased incidence of gastrointestinal cancer.Because they generally start in the second decade of life, and are usually lifelong conditions, they have a major detrimental effect on the social, professional and economic life of the affected individual. Direct costs of these diseases to the NHS are approximately 1 billion pounds per year. The methods used to achieve a diagnosis of these conditions are imprecise, and largely descriptive. They consist of X-rays, colonoscopy, and as a more recent development, an imaging capsule can be swallowed. Small bits of the lining of the bowel can be removed for histological examination, which produces a subjective assessment of the microscopic appearance. The development of new molecular technologies has created the possibility of identifying the basic mechanisms causing these diseases, and the molecules responsible, which could lead to more accurate diagnosis and the development of more effective treatment.We have established that:These two diseases are very different. CD is an immunodeficiency in which the patient's early inflammatory response to bacteria entering the tissues is ineffectual, leading to defective removal of bacteria from the tissues, resulting in chronic inflammation. By contrast, inflammation in UC is abnormally strong. CD affects the large and small bowel and the inflammation penetrates deep into the tissues whereas UC is confined to the superficial lining of the large bowel.In CD the macrophage, a conductor of the immunological orchestra, is defective in a large proportion of patients leading to impaired inflammation. To identify the reason for this we collected macrophages from patients and healthy control subjects and found several genes to be expressed at abnormally low levels in patients. So far we have tested two of these, ADAMDEC1, an enzyme that chops up proteins, and Optineurin, a linker molecule that is involved in moving proteins inside cells. We developed fish and mice that were lacking either ADAMDEC1 or Optineurin in order to investigate their role in bowel inflammation, and the absence of either gene caused an increased inflammation in the bowels of the animals, consistent with the effect observed in patients.We applied a similar approach to investigating the cause of UC. In this case we examined the pattern of expression of genes in the lining of the bowel, because of prior research indicating that this lining was abnormally friable in these patients. We discovered two genes that were translated at abnormally low levels in significant numbers of patients. One, Claudin 8, is involved in holding the lining cells together, and virtually nothing is known about the other, FAM5C. We wish to perform a similar study on bowel samples from patients with UC from Iceland, where the disease is very common and there is a small gene pool.We will characterise these four proteins in order to better understand their function and to determine how they predispose to the development of IBD. We would also like to investigate some of the other strong candidate genes that we have identified. IBD associated molecules might be very useful in molecular diagnostic tests.Finally we will attempt to correct the expression of target genes in either the macrophage or bowel by using drugs and/or gene replacement therapy, with the hope of identifying targeted IBD therapies.Our research programme is designed to identify and characterise molecules and mechanism responsible for the development of IBD, which will lead to improved diagnosis and treatment of these conditions.