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: 8053921
• 负责人: BERNHARD HENNIG
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053921
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Atherosclerosis; Blood Vessels; CAV1 gene; Cardiovascular Diseases; Cause of Death; Caveolae; Caveolins; Cells; 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; 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，一种慢性炎症性疾病，仍然是美国的头号死因。 已经确定了许多动脉粥样硬化发展的危险因素，包括肥胖， 高脂血症和暴露于超级基金化学品如持久性有机污染物（例如， RGBs）。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导 通过暴露于共面PCB可以被生物活性化合物如类黄酮显著下调， 这些事件也可以被细胞脂质环境改变。关于营养的机制知之甚少。 调节环境毒性。膜脂质结构域如小窝在细胞中特别丰富， 内皮细胞，其中它们被认为在内皮囊泡的调节中起主要作用。 贩卖人口最近，小窝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。我们还假设抗炎药 类黄酮抗化学损伤的特性可被ω-3脂肪酸增强， 或者被欧米茄-6脂肪酸减少。这些假设将在体外和体内进行测试，通过研究 多氯联苯与膳食成分如脂肪酸和类黄酮的相互作用。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在 炎症结果。我们建议探索新的机制，营养介导的调制， 超级基金化学毒性，我们提出的研究结果将导致新的营养 在接触超级基金化学品的人群中进行治疗干预。超级基金 化学品暴露，特别是像多氯联苯这样的持久性有机污染物，与高风险有关 心血管疾病的风险。项目1打算调查这些人使用的机制， 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将侧重于营养干预手段，通过阻断这些目标， 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。