Development of functional 3D human intestinal mucosae to replace rodent models and improve the predictive accuracy of existing in vitro systems

Current investigations of intestinal absorption and secretory function, frequently involve the use in vivo models or ex vivo animal tissue transport models. However, due to the complexities of the in vivo environment and difficulty to standardize, detailed mechanistic studies are difficult to interpret in such animal systems. In addition, there are differences between animal origin and human tissues that influence absorption kinetics, hence, caution should be taken when extrapolating findings from animal models. Several simplistic cell-based culture models have been developed to better understand drug intestinal permeability in humans. These primarily include cells grown as monolayers on a two-dimensional (2D) substrate, for example, the Caco-2 cells have widely been adopted by the pharmaceutical industry for screening assays.

However, such models have known limitations: they are under developed, they only partly recapitulate the structure of the intestinal mucosa; and they have several important deficits including: lack of other cell types (mucus producing Goblet cells); lack of organized three dimensional (3D) structure; and absence of inter-cellular signaling between the epithelium and underlying stromal tissues. Moreover there are functional deficits in these models including differences in permeability and activity of epithelial pump proteins that play a role in the absorption and secretion.

There is significant demand to create appropriate intestinal models with improved structure and function. We hypothesise that a 3D intestinal mucosal construct will possess more realistic tissue-like structure and function compared to existing 2D epithelial models and a humanized system will overcome some of the limitations associated with animal tissue models. The aim of this study is to demonstrate the superiority of a human 3D intestinal mucosa model to evaluate the function of the epithelial barrier in health and disease.

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PhD Studentship

Status:

Active

Principal investigator

Professor Stefan Przyborski

Institution

Durham University

Co-Investigator

Professor Stuart Wilson

Grant reference number

NC/N00289X/1

Award date:

Oct 2016 - Sep 2019

Grant amount

£90,000