Effect of Nuclear Hormone Receptor Stimulation in Oral and Skin Epithelium

Oral epithelium from around the body exhibits similar properties and play key roles in protecting the underlying host tissues from bacterial invasion. These tissues play an active role in tissue defence and they have demonstrable anti-inflammatory and antioxidant properties and can respond to bacterial challenge by releasing defence-related molecules [e.g. antimicrobial peptides (AMPs)]. However once the epithelial barrier becomes breached, due to chronic inflammation, frustrated healing can result in ulceration of the epithelial covering. Modulation of the hyper-inflammatory response at an early disease stage and repopulation of the ulcerated wounds by induction of proliferation and differentiation of epithelial progenitors has the potential to ameliorate pathogenesis and maintain barrier function.
Nuclear hormone receptors are a family of ligand activated proteins located on the nuclear membrane and when bound activate transcription within the cell nucleus. These switches control the development and differentiation of a variety of organs and tissues including epithelium, bone, brain and reproductive systems. NHR family members include PPAR, LXR, FXR and RXR; and their specific activation can lead to a variety of cellular responses including maintenance of tissue integrity (e.g. via tight junction expression), cell proliferation, differentiation, anti-inflammatory effects, as well as stimulating increases in levels of antioxidant and AMPs.
We hypothesis that modulation of nuclear hormone receptor signalling in skin and oral epithelium will maintain barrier function, tissue defence and homeostasis as well as promoting repair-associated cellular responses. This proposal therefore aims to investigate the individual and combinatorial roles of NHRs on skin and oral epithelium using in vitro 2D & 3D culture model systems. Commercially available materials and ligands (GSK) will be assayed for their ability to activate NHR signalling, in particular to promote differentiation and anti-inflammatory effects in oral and skin epithelium model systems.