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中都是至关重要的，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，特别是与患者导向的研究有关。本课题是一个合理的延伸，将进行以下研究：1)大剂量补充α -生育酚（AT）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)碧萝芷酚单用及联用AT对氧化应激指标的影响；3) N-3 PUFA与AT对炎症和LDL氧化的相互作用；4) HMG-CoA还原酶抑制剂对血浆残余脂蛋白水平的影响；5)非裔美国人和白种人心血管危险因素的演变；6) AT对炎症作用的剂量效应研究。氧化应激的测量包括血浆氧化，通过测定蛋白质羰基，LDL氧化易感性和尿液f2 .异前列腺素的定量。将要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、sp -选择素和c反应蛋白的水平。在活化单核细胞中检测的功能包括超氧阴离子、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，我们将通过EBCT确定同型半胱氨酸和肺炎衣原体在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NFkappa-b活性来获得机制见解。这些研究与德克萨斯大学西南分校的教学课程和临床暴露相结合，为以患者为导向的研究的导师提供了良好的培训基础。该提案中概述的研究显然增强了PI的长期目标，因为他的主要兴趣是营养因子对脂蛋白和动脉粥样硬化关键细胞的作用。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.