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 ß-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/ß-catenin to cell membranes and FOXO1 to the cytoplasm. E.coli LPS,
a TLR4 agonist, reverses this behavior and directs FOXO1 and ß-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, ß-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 ß-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.