Myd88 mediated Anti-Fibrotic effects of Folic Acid treatments in management of Drug-Induced Gingival Overgrowths
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Drug Induced Gingival Overgrowth (DIGO) is a disfiguring side effect of three main drug categories namely, anti-convulsants, calcium channel blocking agents and immunosuppressants. Several conventional treatments are currently available but have a high recurrence rate as high as 40%. Moreover, switching or discontinuation of the causative medication may impact the medical treatments. Therefore, new preventive and treatment strategies are currently needed. While the precise etiopathological mechanism of DIGO remains unclear, a role for the inflammation in mediating the fibrotic responses has been investigated. Previous work in the lab noted a key role for Myd88 in facilitating TNF-α secretion that promoted TGF-β mediated collagen synthesis. Further, prior studies had noted efficacy of local delivery of folic acid (FA) in managing DIGO treatment. Based on these observations, this thesis examined the role of Myd88 in mediating folic acid treatments for DIGO in an animal model and human patient samples. This work developed a novel anterior suture and drug-induced mouse model of DIGO that was used to examine the efficacy of FA by controlled local delivery (gel) and water supplementation. A comprehensive set of assays including digital 2D planimetry, 3D volumetric digital imaging, histology, immunostaining and western blots were used to confirm disease induction and response to treatments. Using a transgenic mouse model, the role of Myd88 was confirmed in mediating this process. Finally, immunohistochemical analyses confirmed a role of upregulated MyD88 in DIGO tissues. In summary, this work demonstrated a key role of Myd88 in mediating efficacy of folic acid in managing DIGO that offers an innovative, novel approach in managing gingival fibroses. These findings could be clearly extrapolated to other sites of pathological fibroses.