The candidate development plan is in 3 phases: phase 1- completion of the PhD, phase 2- completion of specialty training in orthodontics, phase 3- full time research with the goal of submitting a first ward application. The candidate's long-term objective is a career in academic dentistry that will combine an active research career in the basic sciences with the teaching and practice of orthodontics. Boston University GSDM is a leading dental research institution ranking 9th in the nation in dental research funding. The Mentor, the Dean and the Chair of the Department are committed to providing staff, facilities and resources necessary for faculty development and training of the future faculty that will combine active research career with clinical specialties. Research Plan: Neutrophils from patients with Localized Aggressive Periodontitis (LAP) present a hyper-inflammatory phenotype thought to contribute to the pathogenesis of this disease. The phenotype is characterized by increased pro-inflammatory activities including increased secretion of superoxide. The main goal of this proposal is to elucidate the intracellular signaling pathways leading to increased superoxide production in LAP neutrophils. LAP neutrophils have altered cytosolic and membranous protein kinase C (PKC) activity. We hypothesize that different PKC isoforms may be chronically activated in the membrane of LAP neutrophils leading to chronic activation and assembly of the oxidase. Phosphorylation of p47phox, a central subunit of the NADPH oxidase, is an important step in the activation and assembly of the oxidase. p21-activated kinase 2 (PAK2) is another kinase able to phosphorylate p47phox. PAK 2 phosphorylation is increased in LAP neutrophils. Both pathways of activation of the NADPH oxidase will be characterized, including the specific isoforms of PKC that are active in health and disease, and the specific phosphorylation sites of PAK2 that are responsible for activation or inhibition of the NADPH oxidase. ? ?
