Novel contrast enhanced ultrasound imaging approaches to understand and treat gastrointestinal disease

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Novel contrast enhanced ultrasound imaging approaches to understand and treat gastrointestinal disease. This project will use ground-breaking imaging approaches to provide novel insights into the physiology and pathophysiology of the gastrointestinal tract, and a translational platform for the design and evaluation of new drugs for gastrointestinal disease.Collaborative work between the Departments of Medicine and Bioengineering, and Sosei Heptares, an SME creating new medicines which target GPCRs, has used contrast enhanced ultrasound (CEUS) to non-invasively image the rodent gut at unprecedented resolution.We now intend to further develop this approach with ultrafast and super-resolution ultrasound, to give a resolution of ~10microM. This will allow investigation of microcirculatory changes in the gut with unprecedented accuracy, permit the study of inflammation and epithelial dysfunction in rodent models of gut disease, and longitudinal measurements of the response, including mucosal healing, to new therapeutic agents.Hypothesis: CEUS will facilitate our understanding of gut physiology and pathophysiology, and will aid the development of new therapies for gut disease.Aims: 1) To optimise the CEUS methodology to increase resolution and permit highly detailed analysis of the gut microcirculation, and to validate against current invasive methods. 2) To use this imaging approach to assess microcirculatory blood flow in the rodent gut in response to physiological challenges that alter epithelial function and inflammation, including high fat intake, ageing and stress. 3) To use this imaging approach to assess chronic changes in microcirculatory blood flow in the rodent gut in response to agents and genetic changes (e.g. transgenic mice with altered NOD2 or IL23R expression) which model inflammatory bowel disease and can alter villus structure, epithelial function, autophagy/apoptosis, fibrosis and inflammatory processes. Measurements will be validated using histology and protein and gene expression studies.4) To use CEUS to investigate the effect of specific GPCR ligands on microcirculatory blood flow and mucosal healing in these chronic rodent models of inflammatory bowel disease. 5) To develop this imaging approach to investigate epithelial turnover and repair in other tissues where it is important in pathophysiology, such as the lung and the kidney. This project will thus make validate a novel imaging approach for gut imaging to provide novel insight into physiology and gastrointestinal disease, and evaluate new therapeutic agents for gastrointestinal disease. We hope to also show the potential of this CEUS in the study of other tissues, providing a novel and wide ranging translational platform with significant impact on the reduction and refinement of in vivo studies.