Regulation of epithelial barrier

项目总结 牙周炎和种植体周围炎是一种口腔疾病，其特征是口腔动态平衡的丧失和诱发 发炎。尽管在结缔组织中发生的下游炎症事件一直很好 认识到，在这些疾病中涉及上皮屏障功能的调节通路尚未被 进行了详细的探索。在这项研究中，我们旨在确定控制上皮屏障的关键时空机制。 功能。尽管人们认识到上皮屏障功能是至关重要的，但它的调节机制还不是很清楚。 为了解决这一问题，已经开发了体内和体外的实验模型，如口腔外用装置。基座 在PREL数据上，我们将研究FOXO1，E-钙粘蛋白和β−连环蛋白在维持和丢失 屏障功能是通过细菌诱导信号实现的。初步数据显示，压力增加 上皮性屏障，将E-钙粘蛋白/β−连环蛋白导向细胞膜，将FOXO1导向细胞质。E.ColiLPS， 一种TLR4激动剂，逆转这一行为，并将FOXO1和β−连环蛋白引导到细胞核和细胞膜 E-钙粘附素。这些数据可作为从机械上研究机械压力对 促进上皮完整性及其破坏的大肠杆菌和核杆菌，一种重要的口腔细菌， 使用口外平台(Aim1)。接下来，我们将研究上皮细胞如何附着在钛上 在研究中影响屏障功能，这将使我们深入了解种植体周围炎症的重要过程。 具体地说，我们将研究角质形成细胞-钛作为基础基质的相互作用如何调节 角质形成细胞在压力或E.ColiLPS和F.核细菌(AIM2)的存在下。最后，我们将调查 与体内炎症组织相比，FOXO1、β−连环蛋白和E-钙粘蛋白在健康组织中是如何调节的。 动物实验将涉及机制研究，以检验上游事件在屏障功能中的作用 通过体内角质形成细胞中FOX01和TLR4的谱系特异性缺失，来检测β−连环蛋白的异常调节， E-钙粘附素与紧密连接的形成。类似的研究将在非人类组织中进行。 牙周炎和种植体周围炎患者的牙龈炎症，以确定是否相似 在这些疾病过程中发生了失调(Aim3)。鉴于公认的基本重要性， 口腔疾病的复杂性，这些研究可能为确定治疗口腔疾病的新靶点铺平道路 牙周炎和种植体周围炎。

Project summary Periodontitis and peri-implantitis are oral diseases characterized by loss of oral homeostasis and induction of inflammation. Although downstream inflammatory events that occur in connective tissue have been well recognized, the regulatory pathways involved in epithelial barrier function in these diseases has not been explored in detail. In this study, we aim to identify key spatiotemporal mechanisms that control epithelial barrier function. Although it is recognized that epithelial barrier function is critical it's regulation is not well understood. To address this, in vivo and in vitro experimental models, such as Epi-oral device, have been developed. Based on Prel Data we will investigate the role of FOXO1, E-cadherin and β−catenin in the maintenance and loss of barrier function through bacteria induced signaling. Preliminary Data demonstrate that pressure enhances epithelial barrier and directs E-cadherin/β−catenin to cell membranes and FOXO1 to the cytoplasm. E.coli LPS, a TLR4 agonist, reverses this behavior and directs FOXO1 and β−catenin to the nucleus and from cell membranes E-cadherin. These data serve as the basis to mechanistically investigate the role of mechanical pressure on promoting epithelial integrity and its disruption by E.coli LPS and F. nucleatum, an important oral bacterium, by use of the Epi-oral platform (Aim1). Next, we will investigate how epithelial attachment to titanium may affect barrier function in studies that will give insight into processes that are important in peri-implantitis. Specifically, we will examine how the interaction of keratinocytes-titanium, as underlying matrix, regulates keratinocytes in the presence of pressure or E.coli LPS and F. nucleatum (Aim2). Finally, we will investigate how FOXO1, β−catenin and E-cadherin are modulated in healthy tissue compared to inflamed tissue in vivo. Animal experiments will involve mechanistic studies to examine the role of upstream events in barrier function by lineage specific deletion of FOXO1 and TLR4 in keratinocytes in vivo, to examine dysregulation of β−catenin, E-cadherin and the formation of tight junctions. Similar studies will be examined in human tissue from non- inflamed gingiva, and gingiva from patients with periodontitis and peri-implantitis sites to determine if similar dysregulation occurs in these disease processes (Aim3). Given the recognized fundamental importance of the complexity in oral diseases, these studies may pave the way to identify novel targets for treatments against periodontitis and peri-implantitis.