• B.S. 1983, Cook College, Rutgers University
  
• PhD, 1990, The Johns Hopkins School of Medicine

One of our research projects concerns the role of PLA2 and lipid mediators in the host response in periodontal disease. In these experiments, we are studying human subjects who have Localized Aggressive Periodontitis (LAgP), a severe inflammatory disorder of the gums that affects adolescents. LAgP is an infectious disease and has been associated with at least two virulent oral pathogens, A. actinomycetemcomitans and P. gingivalis. These bacteria colonize the oral cavity and can cause tissue damage through the secretion of proteases and leukotoxins. In addition, the oral pathogens stimulate the host immune system and the ensuing inflammatory response is largely responsible for the tissue damage that is observed in LAgP patients. Compared to age- and race-matched periodontally healthy people, LAgP patients produce large amounts of one class of antibody, IgG2. Much of this antibody is directed against the oral bacteria that are associated with the disease and our studies suggest that the antibody helps to control the disease and limits its severity. Our recent experiments indicate that two lipid mediators, prostaglandin E2 (PGE2) and platelet-activating factor (PAF) are essential for IgG2 production in LAgP patients. Both of these lipids are associated with the inflammatory response and are products derived from PLA2. At present, we are characterizing the PLA2s that are expressed by LAgP patients and periodontally healthy people to determine if LAgP patients express a different panel of PLA2s and / or produce elevated levels of PGE2 and PAF. In E2 addition, we are studying a specific form of sPLA2, PAF acetylhydrolase (PAFAH). PAFAH is the enzyme that catabolizes PAF and our studies indicate that its expression is lower in LAgP patients than in people who are periodontally healthy. Finally, our recent experiments indicate that a specialized antigen presenting cell, the dendritic cell has a rather unique PAF metabolism and plays a critical role in the production of IgG2. Therefore, we are also performing experiments to characterize these cells with respect to the expression of PAFAH, responses to PAF, and the production of lipid mediators like PAF and PGE2. The panel below shows a model depicting our studies in this area. Together, these studies should further elucidate the roles of the lipid mediators in pathogenesis and the antibody response in LAgP. Armed with this knowledge, we may be able to develop strategies to promote the protective roles of the lipid mediators while suppressing their roles in pathogenesis.

In another research project, we are interested in understanding how PLA2 regulates the amount of phospholipid in mammalian cell membranes. To this end, we have prepared cells that over express the rate limiting enzyme in the synthetic pathway for phosphatidylcholine (PC), an abundant and essential phospholipid in mammalian cell membranes. Interestingly, although these cells make more PC than do parental cells, they also exhibit increased expression of iPLA2. Presumably, this occurs to balance the increase in PC synthesis and ensure that the mass of PC in the membrane remains relatively constant. However, cells must double their phospholipid content during the cell cycle to allow for the production of daughter cell membranes. Several lines of evidence indicate PC and other phospholipids accumulate during S phase due to a decrease in their catabolism. Our data indicate that phospholipid accumulation can be attributed to a decrease in iPLA2 activity during G1. In addition to allowing for phospholipid accumulation, we predict that this loss of iPLA2 activity also prevents the accumulation of modified fatty acids that suppress the expression of the cyclin D proteins that are essential for cells to progress from G1 to S phase. Thus, iPLA2 has several essential roles in phospholipid metabolism and these impinge on such basic physiological processes as cell division. At present, we are determining the mechanisms that regulate iPLA2 activity during the cell cycle and that regulate the expression of iPLA2. Our preliminary studies suggest that iPLA2 activity is regulated through an alternative splicing event that generates truncated iPLA2 proteins that suppress the activity of the enzyme. The expression of iPLA2 appears to be regulated by sterol regulatory element binding proteins (SREBPs), a family of transcription factors whose biological activities are modulated by cholesterol and other sterols in mammalian cells. This observation is intriguing, as it indicates a coordinate regulation of sterol and phospholipid metabolism. Such regulatory mechanisms may be essential, as the relative amounts of sterol and phospholipid in cell membranes must be tightly controlled to maintain membrane integrity and fluidity. The panel below shows a model depicting our studies in this area. Although these studies are not relevant to a specific disease, they are important because they yield insights into the basic mechanisms of phospholipid metabolism and cell homeostasis.