Gingival overgrowth is a side effect of specific medications, and occurs as inherited and idiopathic forms (HGF). The condition impairs mastication, and predisposes affected individuals to systemic complications. Although gingival overgrowth lesions appear clinically similar, our studies have shown that the molecular and cellular features of gingival overgrowth vary as a function of the cause. Phenytoin-induced gingival overgrowth and HGF lesions are highly fibrotic and contain high levels of connective tissue growth factor (CTGF); whereas cyclosporin A induced overgrowth is less fibrotic, and contains low amounts of CTGF; and nifedipine-induced gingival overgrowth is intermediated in all respects. Recent studies have identified tissue specific pathways that provide the mechanism for elevated CTGF expression in fibrotic gingival tissues, and potential therapeutic strategies. In addition, we have published evidence that CTGF promotes extracellular matrix deposition via alpha-6 and beta-1 integrins. Preliminary data suggest that the process of epithelial- mesenchymal transition (EMT) contributes to all forms of gingival overgrowth; and that a critically important matrix metalloproteinase (MMP-13) is down regulated in fibrotic forms of gingival overgrowth. Thus, two aims are proposed.
In Aim 1 we will establish that EMT occurs in all forms of human gingival overgrowth in vivo, and we will evaluate the mechanism of inhibitors of EMT to block progression of abnormalities in in vitro studies of primary gingival epithelial cells and fibroblasts.
Aim 2 proposes to evaluate the hypothesis that CTGF regulates extracellular collagen processing enzymes and a matrix metalloproteinase (MMP-13), thereby increasing net extracellular matrix accumulation. Proposed studies will determine CTGF stimulated signal transduction pathways and regulated downstream genes that lead to increased extracellular matrix deposition. These studies take advantage of a peptide that inhibits CTGF-dependent extracellular matrix deposition that we have recently identified. The proposed experimental approach utilizes in situ analyses of human gingival overgrowth tissues, and primary cultured human gingival epithelial cells grown in monolayer and three dimensional configurations. Studies will identify novel cellular and molecular pathways that contribute to gingival overgrowth. Findings will have relevance to fibrosis in both oral and non-oral tissues in which CTGF is a contributing factor, thus potentially identifying new therapeutic strategies in various tissues. ? ? ?
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