Project 1: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction

动脉粥样硬化是一种慢性炎症性疾病，在美国仍然是头号死因。 已经确定了许多导致动脉粥样硬化发展的危险因素，包括肥胖、 高甘油三酯血症和暴露于超级基金化学品，如持久性有机污染物(例如， RGB)。据报道，植物性生物活性食品成分具有抗氧化和消炎作用。 属性。我们的初步数据表明，内皮细胞功能障碍和炎症事件导致 通过暴露于共面多氯联苯，可以显著下调生物活性化合物，如黄酮类， 这些事件也可以被细胞内的脂质环境改变。人们对营养的作用机制知之甚少 环境毒性的调控。膜脂结构域，如小凹，尤其丰富 被认为在调节内皮泡中起主要作用的内皮细胞 贩卖人口。最近，小凹也参与了细胞信号转导的调节。 因此，我们假设小窝在细胞对超级基金污染物、脂质和 亲脂性生物活性化合物，如类黄酮类。我们还假设抗炎药 Omega-3脂肪酸可增强类黄酮类化合物的抗化学损伤性能并拮抗其作用 或被omega-6脂肪酸减少。这些假说将通过研究在体外和体内得到验证 多氯联苯与膳食成分的相互作用，如脂肪酸和类黄酮。重要的是，我们会 利用缺乏小窝蛋白基因的细胞和小鼠模型来确定小窝病毒在小窝病毒感染中的作用 炎症结果。我们建议探索营养调节的新机制。 超级基金化学毒性，我们建议的研究结果将导致新的营养 对暴露于超级基金化学品的人群的建议和治疗干预。超级基金 接触化学物质，特别是像多氯联苯这样的持久性有机污染物，已被认为与高风险有关 心血管疾病对公众的影响。项目1打算调查这些机构使用的机制 导致疾病的化学物质，特别是由膜结构域控制的信号通路， 小窝。项目1将重点放在通过阻断这些目标进行营养干预的手段，从而 提出保护公众免受超级基金化学品暴露的有害影响的方法。

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-inflammatory properties. Our preliminary data suggest that endothelial cell dysfunction and inflammatory events induced by 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 nutritional modulation of environmental toxicity. Membrane lipid domains such as caveolae are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking. 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, and lipophilic bioactive compounds such as flavonoids. We also hypothesize that the anti-inflammatory properties of flavonoids against chemical insults may be enhanced by omega-3 fatty acids and antagonized or lessened by omega-6 fatty acids. These hypotheses will be tested in vitro as well as in vivo by studying the interactions of PCBs with dietary components such as fatty acids and flavonoids. Importantly, we will use cell and mouse models lacking the caveolin gene to determine the involvement of caveolae in inflammatory outcome. We propose to explore novel mechanisms of nutrient-mediated modulation of Superfund chemical toxicity, and the outcome of our proposed study will lead to novel nutritional recommendations and therapeutic interventions in populations exposed to Superfund chemicals. Superfund chemical exposure, specifically persistent organic pollutants like PCBs, has been linked to a heightened risk of cardiovascular disease to the public. Project 1 intends to investigate the mechanisms used by these chemicals 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 thus proposing means of protecting the public from the harmful effects of Superfund chemical exposure.