Pathogenic role of peroxisome proliferator-activated receptor alpha in periodontitis

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Project Summary Periodontitis is an important public health problem among adults in the U.S., with major economic costs for prevention and treatment and significant impact on quality of life. Un-controlled periodontitis can cause ex- tensive tooth loss, jaw bone deterioration, and increased risk of developing systemic diseases. Conventional treatments that rely on antibiotics and mechanical removal of dental plaque are transiently effective because they indirectly address the inflammation and related immune responses that underlie periodontitis, but do not directly impact pathogenesis. Thus, there is a compelling need to investigate novel target molecules which di- rectly modulate pathogenesis for both inflammation and bone loss in periodontitis. It has been demonstrated that PPARα agonists (PPARαA), which is PPARα specific, have robust protective actions limiting inflammation in autoimmune disease, modulating inflammation. Our preliminary data suggest that a PPARαA, fenofibrate, has the potential to reduce periodontal inflammation and bone resorption in experimental periodontitis mouse mod- els, suggesting that the pathological role of PPARα in periodontitis deserves further investigation. We propose to test the hypothesis that PPARα not PPARβ or PPARγ plays important pathological roles in periodontitis. To that end, two distinct but complementary specific aims are proposed. Aim1 will determine that PPARα not PPARβ or PPARγ has expression level changes in periodontitis. Aim 2 will determine PPARα Knockout or overexpres- sion will affect inflammation and bone loss in experimental periodontitis mouse model. The understanding of expression level change of PPARα in periodontitis investigated during Aim1 will provide the foundation for Aim2. The goal is to reveal the role of PPARα in inflammatory regulation and in modulation of bone homeostasis during periodontal diseases. Building on previous experience and both Aim1 and Aim2 will lead to the development of novel, PPARα targeted therapies for periodontits and various other oral diseases. Successful completion of this project will lead to better understanding of the molecular and cellular role of PPARα in periodontitis, and translate this knowledge to develop an application system to achieve sustained release with noninvasive local delivery for the clinical treatment of periodontitis.