CLINICAL STUDIES IN NUTRITION AND METABOLISM

心血管疾病是美国发病率和死亡率的主要原因。 目前的证据表明，炎症和氧化应激在动脉粥样硬化形成中至关重要，饮食中的抗氧化剂可能是有益的。自1988年以来，候选人的小组在该领域进行了重要的观察，特别是因为它涉及到以病人为导向的研究。在这个合理的扩展方案中，将进行以下研究：1）高剂量α-生育酚（AT）补充对冠心病患者LDL氧化、单核细胞促动脉粥样硬化活性和颈动脉粥样硬化的影响; 2）碧萝芷单独和与AT联合对氧化应激指标的影响; 3）N-3 PUFA和AT对炎症和LDL氧化的相互作用; 4）HMG-CoA还原酶抑制剂对残余脂蛋白的血浆水平的影响; 5）非裔美国人和高加索人中不断发展的心血管危险因素;以及6）AT对炎症影响的剂量反应研究。氧化应激的措施包括通过测定蛋白质羰基的血浆氧化、LDL氧化敏感性和尿F2. 将研究的炎症标志物包括。血浆可溶性粘附分子s-ICAM、s-VCAM、sE-选择素和sP-选择素以及C-反应蛋白水平。将在活化的单核细胞中测定的功能是超氧阴离子、IL-1 β、TNF-α、组织因子和单核细胞内皮粘附。在项目V中，除了研究氧化应激和炎症的测量外，我们还将确定同型半胱氨酸和肺炎衣原体在EBCT预测动脉粥样硬化中的作用。在项目VI中，将通过研究PKC，5-LO和NF κ B活性来获得机制见解。 这些研究加上教学课程和临床暴露在UT西南提供了一个很好的培训基地，为学员在病人为导向的研究。本提案中概述的研究明显增强了PI的长期目标，因为他的主要兴趣是营养因子对脂蛋白和关键细胞在动脉粥样硬化形成中的作用。总的来说，这些研究肯定有助于我们对动脉粥样硬化的理解。

Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Current evidence suggests that both inflammation and oxidative stress are crucial in atherogenesis and that dietary antioxidants may be beneficial. Since 1988 the candidate's group has made significant observations in the area, especially as it relates to patient oriented research. In this proposal, which is a logical extension, the following studies will be undertaken: 1) The effect of high dose alpha-tocopherol (AT) supplementation on LDL oxidation, monocyte pro-atherogenic activity and carotid atherosclerosis in patients with coronary artery disease; 2) The effect of pycnogenol alone and in combination with AT on measures of oxidative stress; 3) Interaction between N-3 PUFA and AT on inflammation and LDL oxidation; 4) The effect of HMG-CoA reductase inhibitors on plasma levels of remnant lipoproteins; 5) Evolving cardiovascular risk factors in African Americans and Caucasians; and 6) A dose response study on the effect of AT on inflammation. The measures of oxidative stress include plasma oxidation by assaying protein carbonyls, LDL oxidative susceptibility and the quantitation of urinary F2.isoprostanes. Inflammatory markers that will be studied include. plasma levels of soluble adhesion molecules s-ICAM, s-VCAM, sE-selectin and sP-selectin and C-reactive protein. The functions that will be assayed in activated monocytes are superoxide anion, IL-1beta, TNF-alpha, tissue factor, and monocyte endothelial adhesion. In Project V, in addition to studying measures of oxidative stress and inflammation, we will determine the role of homocysteine and Chlamydia pneumoniae in predicting atherosclerosis by EBCT. In Project VI mechanistic insights will be gained by studying PKC, 5-LO and NFkappa-b activity. These studies coupled with didactic courses and clinical exposure at UT Southwestern provide an excellent training ground for mentorees in patient oriented research. The studies outlined in this proposal clearly enhance the long-term objectives of the PI, since his major interest is in the role of nutritional factors on lipoproteins and critical cells in atherogenesis. These studies in aggregate will definitely contribute to our understanding of atherosclerosis.