The tumor necrosis factor (TNF) and TNF receptor (TNFR) families play essential roles in regulating the role of cells during development and inflammatory processes, yet relatively little is known about how they regulate inflammatory responses and wound healing in the oral cavity. We will examine how CD40, CD95 and other TNFR members regulate the fate of gingival epithelial cells (GECs). Very little is known about why children by-in-large re resistant to periodontal disease and what resistance mechanisms break down in individuals who develop early onset periodontitis and the associated tissue destruction in the oral cavity. This project will investigate not only how the fate of GECs is normally regulated but also how oral bacteria influence the growth or death of GECs. These studies will contribute to the understanding of the molecular basis of resistance or susceptibility to initial invasion by oral cavity pathogens. Our specific Aims are: 1) To test the hypothesis that CD40 or CD95 regulate the expression of TNFR family members on GECs, thereby making them susceptible to apoptosis. The ability of Fas mAB, CD40 mAb, soluble TNF- alpha or TRAIL to induce apoptosis of activated GECs will be evaluated. We will test if GECs express CD40L, FasL, TRAIL and TNF-alpha and in particular if Fas ligation may influence death or inflammatory responses in the gingival mucosa; 2) To test the hypothesis that death pathway-associated genes are regulated by CD40 and Fas receptors in GECs. The set of death pathway-associated genes induced in GECs by CD40 will be evaluated in depth for possible roles in regulating epithelial cell fate; 3) To tet the hypothesis that oral bacteria regulate gingival epithelial cell fate and dendritic cell fate. GECs or CD1+ DCs will be exposed to planktonic bacteria or biofilms of periodontopathic Porphyromonas gingivalis (Pg), and an early plaque bacterium. Streptococcus gordonii (Sg). Induction by planktonic Pg or Sg or biofilms of chemokine receptor, TNF/TNFR family members and cell fate genes will be compared. Further understanding of cell death processes in epithelial and dendritic cells could also lead to new insights into how bone formation, regeneration and wound healing in the periodontium are regulated.