Integrated Biology of the GI Tract
The Gut Epithelium
Primary Objectives
- How is the formation of the intracellular junctional complexes that contribute to the glue holding adjacent epithelial cells together regulated?
- What effect does metabolic stress have on epithelial cell integrity and growth?
- What are the mechanisms responsible for changes in the structure (methylation) of DNA in intestinal epithelial cells that are associated with ageing and disease?
- What impact do dietary fats have on epithelial cell health?
This research area is focussed on the mechanisms maintaining mucosal integrity and barrier function as well as the environmental factors, including microbial agents that interact with the epithelium and the impact that age-related loss of crypt homeostasis has on epithelial homeostasis. Defective barrier function and abnormal crypt epithelial proliferation and apoptosis are associated with increased susceptibility to infection and oncogenesis. These changes can result from acquired somatic mutations, which are widely studied in other research centres, but also from physiological adaptation to chronic stress, and from acquired epigenetic aberrations that modify gene transcription. Our research focuses on the mechanisms by which epithelial permeability and barrier function is regulated and the impact metabolic stress and epigenetic aberrations has on age-related changes in epithelial homeostasis, areas in which IFR has developed particular experience and technical expertise.
Mechanisms of regulating epithelial tight junction complexed that are integral to epithelial barrier function. Simon Carding
Intestinal epithelial barrier function is maintained by intracellular junction complexes, of which tight junctions (TJ) are the most apical component. TJ complexes comprise the integral membrane proteins occludin and claudin family members that interact with cytoplasmic plaques consisting of proteins such as zona occludin (ZO) proteins that act as signal transduction complex transmitting signals that influence epithelial proliferation and differentiation. Diseases such as diabetes, cancer, diarrhoea, IBD, multiple sclerosis and allergic disorders are associated with disruption of TJs and alterations in the regulation of occludin.
We have uncovered a role for epithelia-associated (intraepithelial) lymphocytes in maintaining intestinal barrier function. This project will provide evidence of the mechanism by which these lymphocytes promote barrier integrity.
Develop an understanding of the mechanisms of age-related CpG Island (CGI) methylation and determine the impact of diet, metabolism and the gut microbiome. Nigel Belshaw
The role of epigenetic markers as environmentally-responsive modifiers of gene expression in human health and disease is increasingly recognised, and the onset of aberrant CpG island methylation is thought to be the most important epigenetic mechanism operating in the ageing human intestine. Using a combination of in vitro (cell lines and crypts) and appropriate in vivo models we will explore the interactions between the microbiome, the metabolome and the epigenome.
Impact of polyunsaturated fatty acids (PUFA) on colonic homeostasis.Simon Carding
The epidemiological evidence that n-3 PUFAs from marine sources are important in relation to maintenance of colonic health continues to strengthen, whilst the pro-inflammatory effects of n-6 fatty acids from plant sources may also be a matter of concern. This evidence is consistently supported by data from many animal studies. However the underlying mechanisms whereby different fatty acids mediate their effects are still far from clear. Since at least 98% of dietary n-3 PUFAs are absorbed in the small intestine it is probable that their predominant effects on cell proliferation occur via their incorporation from the systemic circulation into the membrane phospholipids of the colonocytes.
Our major area of interest is the impact of PUFAs on low-level inflammation and cytokine signalling in the colon. The overarching hypothesis guiding our experiments is that the host mucosal and cytokine response is modulated according to the type of PUFA.
Fax: +44(0)1603 507723 
