Atherosclerosis, a chronic inflammatory disease, is still the number one cause of death in the United States.Numerous risk factors for the development of atherosclerosis have been identified, including obesity,hypertriglyceridemia and exposure to Superfund chemicals such as persistent organic pollutants (e.g.,RGBs). Plant-based bioactive food components are reported to have antioxidant and anti-inflammatoryproperties. Our preliminary data suggest that endothelial cell dysfunction and inflammatory events inducedby exposure to coplanar PCBs can be markedly down-regulated by bioactive compounds such as flavonoids,events which also can be modified by the cellular lipid milieu. Little is known about mechanisms of nutritionalmodulation of environmental toxicity. Membrane lipid domains such as caveolae are particularly abundant inendothelial cells, where they are believed to play a major role in the regulation of endothelial vesiculartrafficking. More recently, caveolae have also been implicated in the regulation of cell signal transductions.Thus, we hypothesize that caveolae are critical in the cellular responses to Superfund pollutants, lipids, andlipophilic bioactive compounds such as flavonoids. We also hypothesize that the anti-inflammatoryproperties of flavonoids against chemical insults may be enhanced by omega-3 fatty acids and antagonizedor lessened by omega-6 fatty acids. These hypotheses will be tested in vitro as well as in vivo by studyingthe interactions of PCBs with dietary components such as fatty acids and flavonoids. Importantly, we willuse cell and mouse models lacking the caveolin gene to determine the involvement of caveolae ininflammatory outcome. We propose to explore novel mechanisms of nutrient-mediated modulation ofSuperfund chemical toxicity, and the outcome of our proposed study will lead to novel nutritionalrecommendations and therapeutic interventions in populations exposed to Superfund chemicals. Superfundchemical exposure, specifically persistent organic pollutants like PCBs, has been linked to a heightened riskof cardiovascular disease to the public. Project 1 intends to investigate the mechanisms used by thesechemicals resulting in disease, specifically signaling pathways controlled by the membrane domains,caveolae. Project 1 will focus on means of nutritional intervention by blocking these targets and thusproposing means of protecting the public from the harmful effects of Superfund chemical exposure.
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