R01DE031046

Regulation of Epithelial Barrier - Project Summary

Periodontitis and peri-implantitis are oral diseases characterized by the loss of oral homeostasis and the induction of inflammation. While downstream inflammatory events in connective tissue have been well recognized, the regulatory pathways involved in epithelial barrier function in these diseases have not been explored in detail.

In this study, our aim is to identify key spatiotemporal mechanisms that control epithelial barrier function. Although it is recognized that epithelial barrier function is critical, its regulation is not well understood. To address this, in vivo and in vitro experimental models, such as the Epi-Oral device, have been developed.

Based on preliminary 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. However, E. coli LPS, a TLR4 agonist, reverses this behavior and directs FOXO1 and β-catenin to the nucleus and E-cadherin away from cell membranes. These data serve as the basis to mechanistically investigate the role of mechanical pressure in promoting epithelial integrity and its disruption by E. coli LPS and F. nucleatum, an important oral bacterium, using the Epi-Oral platform (AIM1).

Next, we will investigate how epithelial attachment to titanium may affect barrier function in studies that will provide insight into processes important in peri-implantitis. Specifically, we will examine how the interaction of keratinocytes-titanium, as the 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.

Georgetown University

NOT APPLICABLE

93.121 - Oral Diseases and Disorders Research

National Institute of Dental and Craniofacial Research (NIDCR) [HHS - NIH]

Washington, District Of Columbia 200571468 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 300% from $456,254 to $1,824,387.