A Novel Strategy for the Development of Pharmaceuticals in the Treatment of Human Inflammatory Bowel Disease

Inflammation in the intestinal tract is a major health issue in western societies with increasing incidence of ulcerative colitis (UC) and inflammatory bowel disorders (IBD), such as Crohn’s disease. Over 500 million people present with symptoms associated with such diseases and the incidence is increasing, especially in developing urbanized countries. There are currently no suitable model systems to enable the robust and reproducible assessment of new pharmaceutical interventions. There is significant demand for the development of new in vitro alternatives to model human intestinal inflammatory disease to enhance the predictive accuracy of new therapeutics.
We hypothesize that a three-dimensional intestinal mucosal construct will possess more realistic tissue-like structure and function of the gut wall compared to existing epithelial cell culture models. Our humanized system will overcome some of the limitations associated with animal tissue models and existing in vitro methods using human cell lines, and supplement ex vivo approaches. In this project we will build on our track record of developing novel bioengineered human tissue constructs. We have generated preliminary evidence to build a model of the human intestinal mucosa. We will now incorporate immune cells to simulate the inflammatory component observed in inflammatory tissues. We will characterize the model and compare its structure and function directly with samples of human diseased tissue from patients suffering from IBD and ulcerative colitis. This will involve the application of advanced cell technology to optimize the growth of intestinal and immune cells to recreate the inflammatory disease conditions observed in pathological specimens. We will use state of the art cellular and molecular analytical methods to complete in-depth characterization of the model in direct comparison to samples of human pathological tissues. We will determine whether the presence of the immune component and inflammatory reaction results in changes to the function and barrier properties of the gut wall that are symptomatic in inflammatory disease pathology. We will also assess the action of known pharmaceuticals in the treatment of such intestinal diseases and cross compare their activity in our in vitro system to further validate the model. The outcome of this project will be a novel in vitro inflammatory model of the human intestinal mucosa presenting features of the human pathological conditions observed in IBD and ulcerative colitis. The student will gain training in a broad range of modern cell and molecular techniques in the topical area of tissue engineering. They will also experience research in both the academic and industrial sectors.