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，候选人的研究小组在这一领域进行了重要的观察，特别是与以患者为中心的研究有关。在这一合乎逻辑的扩展方案中，将进行下列研究：1)大剂量补充α-生育酚(AT)对冠心病患者低密度脂蛋白氧化、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)碧萝精单独或联合AT对氧化应激指标的影响；3)N-3多不饱和脂肪酸和AT之间的相互作用对炎症和低密度脂蛋白氧化的影响；4)HMG-CoA还原酶抑制剂对血浆残余脂蛋白水平的影响；5)非裔美国人和高加索人心血管危险因素的演变；以及6)AT对炎症作用的剂量效应研究。氧化应激指标包括血浆氧化测定、低密度脂蛋白氧化敏感性测定和尿F2异前列腺素定量。将研究的炎症标志物包括。血浆可溶性黏附分子S-细胞间黏附分子、S-血管细胞黏附分子、sE-选择素和sP-选择素及C反应蛋白水平。将在激活的单核细胞中检测的功能包括超氧阴离子、IL-1β、肿瘤坏死因子-α、组织因子和单核细胞内皮细胞黏附。在项目V中，除了研究氧化应激和炎症的测量方法外，我们还将通过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的活动来获得机理上的见解。这些研究与得克萨斯大学西南分校的授课课程和临床经验相结合，为指导学生进行以患者为中心的研究提供了一个极好的培训基础。这项建议中概述的研究显然加强了PI的长期目标，因为他的主要兴趣是营养因素对脂蛋白和关键细胞在动脉粥样硬化形成中的作用。总而言之，这些研究将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.