INNATE HOST DEFENSE AND ORAL EPITHELIAL CELL FATE

肿瘤坏死因子(TNF)及其受体(TNFR)家族在细胞发育和炎症过程中起着重要的调节作用，但对它们如何调节口腔炎症反应和伤口愈合知之甚少。我们将研究CD40、CD95和其他TNFR成员如何调控牙龈上皮细胞(GEC)的命运。人们对儿童普遍对牙周疾病产生抵抗力的原因以及早发性牙周炎和相关口腔组织破坏的个体的抵抗力机制的破坏知之甚少。该项目不仅将研究GECs的命运是如何正常调节的，而且还将研究口腔细菌如何影响GECs的生长或死亡。这些研究将有助于理解口腔病原体对初始侵袭的抵抗力或易感性的分子基础。我们的具体目标是：1)验证CD40或CD95调节GEC上TNFR家族成员表达从而使其容易发生凋亡的假说。评估Fas单抗、CD40单抗、可溶性肿瘤坏死因子-α或TRAIL诱导活化的GECs凋亡的能力。我们将测试GEC是否表达CD40L、FasL、TRAIL和TNF-α，特别是Fas结扎是否会影响牙龈粘膜的死亡或炎症反应；2)验证死亡途径相关基因在GEC中受CD40和Fas受体调控的假说。CD40诱导的GECs死亡途径相关基因集将被深入评估，以寻找可能在调控上皮细胞命运中的作用；3)检验口腔细菌调控牙龈上皮细胞命运和树突状细胞命运的假说。GEC或CD1+DC将暴露在浮游细菌或牙周病牙龈卟啉单胞菌(PG)的生物膜中，以及一种早期的菌斑细菌。戈登链球菌(Sg)。比较Pg、Sg或生物膜对趋化因子受体、肿瘤坏死因子/肿瘤坏死因子受体家族成员和细胞命运基因的诱导作用。进一步了解上皮细胞和树突状细胞的细胞死亡过程也可能导致对牙周组织中骨形成、再生和伤口愈合的调控的新见解。

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.