Effect of Nuclear Hormone Receptor Stimulation in Oral and Skin Epithelium

来自身体周围的口腔上皮表现出相似的特性，并且在保护下面的宿主组织免受细菌入侵方面发挥关键作用。这些组织在组织防御中起着积极的作用，它们具有明显的抗炎和抗氧化特性，并且可以通过释放防御相关分子[例如抗菌肽（AMP）]来响应细菌的挑战。然而，一旦上皮屏障被破坏，由于慢性炎症，愈合受阻可导致上皮覆盖物的溃疡。通过诱导上皮祖细胞的增殖和分化来调节早期炎症反应和溃疡伤口的再增殖，具有改善发病机制和维持屏障功能的潜力。核激素受体是位于核膜上的配体活化蛋白家族，当结合时激活细胞核内的转录。这些开关控制各种器官和组织的发育和分化，包括上皮、骨、脑和生殖系统。NHR家族成员包括PPAR、LXR、FXR和RXR;并且它们的特异性激活可导致多种细胞反应（例如通过紧密连接表达），细胞增殖，分化，抗炎作用，以及刺激抗氧化剂和AMP水平的增加。我们假设皮肤和口腔上皮细胞中核激素受体信号的调节将维持屏障功能、组织防御和体内平衡以及促进修复相关的细胞反应。因此，该提议旨在使用体外2D和3D培养模型系统研究NHR对皮肤和口腔上皮的个体和组合作用。将测定市售材料和配体（GSK）激活NHR信号传导的能力，特别是在口腔和皮肤上皮模型系统中促进分化和抗炎作用的能力。

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.