Project 1: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction

项目1：超级基金化学品营养与内皮细胞功能障碍

• 批准号: 8249960
• 负责人: BERNHARD HENNIG
• 金额: $ 31.74万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249960
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Atherosclerosis; Blood Vessels; CAV1 gene; Cardiovascular Diseases; Cause of Death; Caveolae; Caveolins; Cell model; Chemical Exposure; Chemicals; Chronic; Critical Pathways; Data; Development; Diet; Dietary Component; Dietary Fats; Dietary Fatty Acid; Dietary Intervention; Disease; Endothelial Cells; Event; Exposure to; Fatty Acids; Flavonoids; Functional disorder; Genes; Health; Hypertriglyceridemia; Incidence; Inflammatory; Inflammatory Response; Intervention; Lead; Link; Lipids; Low-Density Lipoproteins; Mediating; Membrane; Membrane Lipids; Mus; Nutrient; Nutritional; Obesity; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; Pathology; Plants; Play; Polychlorinated Biphenyls; Population; Process; Property; Recommendation; Regulation; Reporting; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Superfund; Testing; Therapeutic Intervention; Toxic effect; United States; base; bioactive food component; cardiovascular disorder risk; in vitro testing; in vivo; mouse model; novel; nutrition; pollutant; prevent; response; superfund chemical; trafficking; uptake

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.

动脉粥样硬化是一种慢性炎症性疾病，仍然是美国的头号死因。 已经确定了许多导致动脉粥样硬化的危险因素，包括肥胖、 高甘油三酯血症和接触超级基金化学品，例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抗炎作用 特性。我们的初步数据表明，内皮细胞功能障碍和炎症事件诱发 暴露于共面 PCB 可以被生物活性化合物（例如类黄酮）显着下调， 也可以通过细胞脂质环境改变的事件。对于营养的机制知之甚少 调节环境毒性。膜脂质结构域（例如小凹）在 内皮细胞，据信它们在内皮囊泡的调节中发挥重要作用 贩运。最近，小凹也与细胞信号转导的调节有关。 因此，我们假设小凹在细胞对超级基金污染物、脂质和脂质的反应中至关重要。 亲脂性生物活性化合物，例如类黄酮。我们还假设抗炎药 omega-3 脂肪酸可能会增强黄酮类化合物抵抗化学损伤的特性并拮抗 或因 omega-6 脂肪酸而减少。这些假设将通过研究在体外和体内进行测试 PCB 与脂肪酸和类黄酮等膳食成分的相互作用。重要的是，我们将 使用缺乏小窝蛋白基因的细胞和小鼠模型来确定小窝蛋白参与 炎症结果。我们建议探索营养介导的调节的新机制 超级基金化学毒性，我们提出的研究结果将带来新的营养 针对接触超级基金化学品人群的建议和治疗干预措施。超级基金 化学品暴露，特别是持久性有机污染物，如多氯联苯，与较高的风险有关 向公众介绍心血管疾病。项目 1 旨在研究这些所使用的机制 导致疾病的化学物质，特别是由膜域控制的信号通路， 小穴。项目1将重点关注营养干预手段，通过阻止这些目标，从而 提出保护公众免受超级基金化学品接触有害影响的方法。