Development of a physiologically-complex model of human intestine for the study of absorption and detoxification'

The intestine is a primary interface between the body and external environment. It controls the uptake of nutrients (including therapeutic compounds) and acts as the first line of defence for detoxification of ingested dietary and environmental xenobiotics (toxins, mutagens, carcinogens). It is now widely accepted that as much model research as possible must be undertaken before any animal studies are considered. However, current gut model research largely relies on transwell culture based on the Caco-2 cell monolayer. This model and other similar ones lack structural and morphological complexity, making them unsuitable for studying efflux transport and metabolic enzymes expressed in the intestinal epithelium.

The aim of this PhD project is to employ a novel tissue engineering technology to generate cell sheets via a unique thermal responsive detachment process and then to construct a more physiologically-complex 3D model of the human small intestine (Lu). The functionality of cell sheets and integrated multicellular in vitro model will be assessed, followed by investigation of the regulatory pathways controlling expression of enzymes and transporters involved in nutrient digestion and absorption (Penny). The model shall also help elucidate the regulatory mechanisms which modulate expression of xenobiotic transporters and metabolic enzymes which govern cellular detoxification capacity.