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

新型超声造影增强成像方法了解和治疗胃肠道疾病。该项目将采用突破性的成像方法，为胃肠道生理学和病理生理学提供新的见解，并为胃肠道疾病新药的设计和评估提供一个翻译平台。医学和生物工程系与Sosei Heptares（一家开发靶向gpcr新药的中小企业）合作，利用对比增强超声（CEUS）以前所未有的分辨率对啮齿动物肠道进行非侵入性成像。我们现在打算用超快和超分辨率超声进一步发展这种方法，使分辨率达到~10微米。这将允许以前所未有的准确性调查肠道微循环变化，允许在肠道疾病的啮齿动物模型中研究炎症和上皮功能障碍，以及对新治疗剂的反应（包括粘膜愈合）的纵向测量。假设：超声造影将促进我们对肠道生理学和病理生理学的理解，并将有助于开发新的肠道疾病治疗方法。目的：1)优化超声造影方法，以提高分辨率，并允许对肠道微循环进行高度详细的分析，并验证当前的侵入性方法。2)利用这种成像方法评估啮齿动物肠道微循环血流对改变上皮功能和炎症的生理挑战的反应，包括高脂肪摄入、衰老和压力。3)利用这种成像方法评估啮齿类动物肠道微循环血流的慢性变化，以应对药物和遗传变化（例如，NOD2或IL23R表达改变的转基因小鼠），这些药物和遗传变化模拟炎症性肠病，可以改变绒毛结构、上皮功能、自噬/凋亡、纤维化和炎症过程。测量结果将通过组织学、蛋白质和基因表达研究进行验证。4)利用超声造影（CEUS）研究特异性GPCR配体对慢性炎性肠病模型小鼠微循环血流和粘膜愈合的影响。5)发展这种成像方法来研究在病理生理学中重要的其他组织（如肺和肾）上皮细胞的更新和修复。因此，该项目将验证一种新的肠道成像方法，为生理学和胃肠道疾病提供新的见解，并评估胃肠道疾病的新治疗药物。我们也希望在其他组织的研究中展示这种超声造影的潜力，为体内研究的减少和改进提供一个新的和广泛的翻译平台。

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.