The long range goal of this investigation is to further our knowledge of the relationship between cellular and molecular structure and function in the inflammatory process, by defining the complex interactions between the neutrophil and its environment. To date, our model for study has been neutrophils from localized juvenile periodontitis (LJP) patients, which exhibit abnormalities of measurable functions. During the previous ten years of this grant, work has focused upon neutrophil surface recognition of environmental signals and signal transduction.
The aims of the previous proposals sought to elucidate the biochemical variations of the LJP neutrophil and how these variations translated into functional abnormalities. As a logical extension of these studies, the currently proposed work will focus upon the biochemical and molecular characterization of abnormalities in signal transduction in a well defined subset of LJP patients with abnormal neutrophil function. Data generated in the previous grant period suggest that there are unusual abnormalities in signal transduction in the LJP neutrophil subsequent to FMLP binding. Functionally, this manifests as a decrease in chemotaxis and an increase in superoxide production in affected cells. Specific observations in LJP include abnormal calcium levels in the cytoplasm, elevated intracellular diacylglycerol concentration, decreased diglycerol kinase activity and decreased protein kinase C activity. There is substantial evidence that clinical LJP is inherited as a autosomal dominant trait. Further, there is data to suggest that in LJP patients neutrophil abnormalities consegrated with clinical disease, suggesting a similar inheritance. The data. however, are not conclusive. The neutrophil defects may also be acquired as result of cell priming. In order to address this problem, stem cells from peripheral blood of LJP and normal subjects will be cultured and differentiated to neutrophils in vitro and functional assays performed in progeny of progenitor cells. Cells grown in this environment free of priming factors should provide direct evidence of genetic transmission or acquired defects of LJP neutrophils. The DG kinase abnormality observed in LJP neutrophils will be characterized by both cloning and sequencing the gene, and extending functional investigations of the enzyme. Continuation of ongoing studies will characterize the regulation of the G protein receptor pathway and the relationship of defective DG kinase activity to other biochemical events.
| Hart, T C; Kornman, K S (1997) Genetic factors in the pathogenesis of periodontitis. Periodontol 2000 14:202-15 |
| Orkin, J L; Braswell, L D (1990) Sialolithiasis in two chimpanzees. J Am Vet Med Assoc 196:1651-3 |
