Relevant Degree Programs
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - April 2022)
Periodontitis is a chronic inflammatory disease, characterized by destruction of the periodontal attachment apparatus including the alveolar bone. Previous studies have provided evidence for the involvement of transforming growth factor beta (TGF-β) signaling in periodontitis progression. TGF-β signaling is responsible for a variety of cellular processes including proliferation, differentiation and apoptosis. The SMAD2 transcription factor lies at the heart of TGF-β intracellular mediators. Previous authors have reported the effect of Smad2 overexpression on multiple mouse tissues (Ito et al 2001), but did not report the role of Smad2 overexpression on the progression of periodontal disease. We hypothesized that Smad2 overexpression alters apoptosis, cell proliferation, and inflammatory cytokine secretions in the junctional epithelium (JE), leading to periodontal attachment loss. A mouse model that overexpresses Smad2 in epithelial cells driven by the cytokeratin 14 promoter (K14) was used to test the hypotheses. The K14-Smad2 mice findings were compared to those observed in wild type (WT) mice that served as controls. The results of the study showed that Smad2 overexpression reduced the histological surface area of JE when compared to WT mice. The reduction of the JE surface area in K14-Smad2 mice was attributed to an increased apoptotic index and a reduced proliferation rate. The overexpression of Smad2 increased the apoptotic index by down regulating Bcl2, an antiapoptotic molecule. Smad2 overexpression also reduced the proliferation rate of the JE cells in K14-Smad2 mice by upregulating c-Myc, which in turn upregulates phosphorylated retinoblastoma P15, and P27. The overexpression of Smad2 resulted in severe alveolar bone loss in the K14-Smad2 mice when compared to the WT controls. Smad2 overexpression resulted in a reduction in the bone density and bone volume in the K14-Smad2 mice when compared to their WT counterparts. The severe alveolar bone loss in K14-Smad2 mice was attributed to an upregulation in tumor necrosis factor alpha (TNF-α) , RANKL and increased osteoclast numbers. In summary the overexpression of Smad2 reduced the histological surface of JE and resulted in severe bone loss that follows a chronic disease pattern in K14-Smad2 mice.
Master's Student Supervision (2010 - 2021)
Objectives: Cleft lip/palate is a common birth defect. It occurs in about one in 700 live births worldwide. In non-syndromic cleft lip/palate, a linkage to TGF-β3 has been shown. Signaling of TGF-β3 is mediated in the cell through the Smad2 protein. During secondary palate fusion TGF-β3 signaling leads to the disappearance of the epithelial midline seam and the confluence of the palatal mesenchyme. TGF-β3 null mice are born with a cleft in the secondary palate, a phenotype that has been rescued by targeted overexpression of Smad2 in the MEE. The goal of this research was to understand the mechanism of palatal fusion in the rescue mice.Methods: The heads of embryos of four different mice models (wild-type, rescue, K14-Smad2 overexpression and TGF-β3 null) were collected at gestational age E14.5 genotyped, fixed and embedded in paraffin. Serial sections were studied for detection of apoptosis and epithelial mesenchymal transition using immunofluorescence. Images were captured with confocal laser microscopy.Results: TGF-β3 null mice developed a cleft in the secondary palate while mice that had both the TGF-β3 null and overexpression K14-Smad2 genotypes had fusion of the secondary palate. The medial edge epithelium of the rescue mice had a much higher ratio of cells with cleaved caspase (31.7% anterior, 33% middle and 35.6% posterior), than in the wild-type mice (0.0% anterior, 5.31% middle and 0.0% posterior). The K14-Smad2 overexpression genotype mice had an increased number of apoptosis positive MEE when compared to the wild-type mice (13.7% anterior, 10.1% middle and 17.6% posterior). The increase in apoptosis was correlated with increased p-Smad2 in the MEE. Conclusions: Smad2 overexpression may have rescued the cleft in the secondary palate by increasing apoptosis in the medial edge epithelium. Thus, the mechanism of rescue is not identical to the events that occur normally during palatal fusion.