Date of Award

2014

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Ruth Borghaei, PhD

Second Advisor

Farzaneh Daghigh, PhD

Third Advisor

Michael McGuinness, PhD

Fourth Advisor

Marcus G Bell, PhD

Abstract

Periodontitis is a chronic inflammatory disease that is characterized by activation of gingival fibroblasts to produce matrix metalloproteinases and other inflammatory mediators that contribute to destruction of tissues surrounding the teeth. In the United States, 22% of adults have a mild form of periodontal disease and 13% suffer from a severe form of the disease. In addition to tooth loss, periodontitis is associated with increased risk of several conditions, including diabetes, osteoporosis, rheumatoid arthritis and cardiovascular disease. Heme oxygenase-1 (HO-1) is activated by a wide variety of stressful stimuli and levels are increased in inflamed tissues. HO-1 degrades free heme, resulting in 3 products, biliverdin (which is quickly converted to bilirubin), iron and carbon monoxide (CO). These products all have antioxidant and anti-inflammatory effects, and HO-1 appears to have an important role in the resolution of inflammation. However, increased expression of HO-1 in certain tumors is associated with increased angiogenesis, metastasis and tumor progression, leading to poor prognosis. It is therefore important to understand how expression of HO-1 is controlled under various conditions. A series of experiments were conducted to determine the effect of tumor necrosis factor alpha (TNFα) on levels of HO-1 mRNA and protein in human gingival fibroblasts (HGF) from patients with periodontitis. Results show that HO-1 mRNA and protein levels decreased over 6 hours in the presence of TNFα. We hypothesized that TNF might decrease HO-1 by increasing levels or activity of the transcriptional repressor Bach1. However, Bach1 mRNA and protein levels did not change significantly over 6 hours after treatment with TNFα, and binding of nuclear factors to the antioxidant response element of the HO-1 promoter remains steady after treatment with TNFα. Although HO-1 expression is sometimes regulated at the level of mRNA stability, there was no change in the rate of HO-1 mRNA degradation following treatment with TNF. Thus, TNFα does decrease HO-1 mRNA and protein expression, however the mechanism of inhibition is still unknown.

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