The long-term objective of this application is to understand the role of NF-kB (nuclear factor kappa B) in the molecular pathogenesis of periodontal diseases using genomic and proteomic approaches. NF-kB is a transcription factor which regulates a variety of immediate early response genes associated with inflammation, immunity and host responses. Periodontal diseases are chronic Gram-negative anaerobic bacterial infections leading to inflammation of the gingiva and destruction of periodontal tissues. Several bacteria including Porphyromonos gingiva/is (P. gingivalis) have been implicated in the initiation and exacerbation of periodontitis. LPS, a major component of the outer membrane of these bacteria, is one of the most potent initiators of host inflammatory and immunological response which results in destruction of periodontal supporting tissue. Recently, the Toll-like receptor (TLR) complex which transduces LPS signaling has been identified. LPS/TLR interaction transduces signaling cascades to activate NF-kB which turns on transcription of inflammatory mediators. Although the TLR signaling complex has been well characterized, the precise mechanisms of NF-kB activation and signaling have not been well studied. Given the critical role of NF-KB in inflammation and host response, NF-kB is likely to play an important role in the molecular pathogenesis of periodontitis. To better understand the role of NF-kB in the molecu]ar pathogenesis of periodontitis, we propose to globa1ly dissect NF-kB-mediated genes and intracellular signaling pathways stimulated by P. gingivalis LPS using genomic and proteomic approaches.
In Aim 1 and Aim 2, we propose to identify P. gingivalis LPS-induced genes regulated by the canonical and non-canonical NF-kB signling pathways on a genome wide basis and explore how the NE-kB-dependent transcription is regulated using genomic and proteomic approaches.
In Aim 3, we will determine whether the canonical and non-canonical NF-kB signaling pathways are activated in inflamed periodontal tissues and explore whether their activation is associated with the gene expression profile induced by P. gingivalis LPS using tissue microarray and protein array. The novel findings from our studies will have important implications in the prevention, diagnosis and treatment of periodontal diseases. ? ?
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