This exploratory proposal will utilize genomic techniques to analyze the molecular interactions that occur between oral bacteria and host epithelial cells associated with the pathogenesis of periodontal disease. Studies will focus on the role of the proteinase-activated receptor (PAR) family in signaling innate immune and inflammatory responses by gingival epithelial cells. Members of this family of receptors are expressed on both gingival epithelial cells and fibroblasts. These receptors signal the presence of danger in the environment, contribute to inflammation and to enhance epithelial cell phagocytosis. However, their role in periodontal disease is poorly understood. Multiple factors produced during the chronic inflammatory response appear to be major factors in the tissue destruction that occurs in periodontal disease. The major microbial species associated with periodontal disease all have proteinases as part of their set of virulence factors. The studies of this proposal will lay the groundwork for further studies on the role of PARs, define a possible new molecular mechanism for pathogenesis of disease, and open the way to understanding new therapeutic targets to prevent or treat periodontal diseases. This work will test the hypotheses (1) that PARs are involved in innate immune function in gingival epithelium and (2) that signaling via PAR-1 and PAR-2 (the most highly expressed members of this family) differentially contributes to the innate immune response in these cells thereby activating different networks of response genes. This work will also examine the possible role of PARs in the recognition of both commensal and pathogenic oral bacteria by gingival epithelial cells.
The aims of the proposal are (1) to characterize the involvement of PAR signaling in upregulation of human beta-defensin-2 and other markers of innate immune activation in oral epithelial cells using the PAR-1 activator, thrombin, and PAR-2 peptide agonist peptide, SLIGRL-NH2, and oral pathogenic and commensal bacteria and (2) to utilize gene array analysis to test the hypothesis that PAR-1 and PAR-2 signaling differentially contributes to the innate immune response in gingival epithelial cells to activate different networks of response genes.
