ENDOTHELIAL CELL FIBRINOLYSIS INDUCED BY WINE PHENOLICS

艾肯斯博士将于1999年7月1日成为UAB心血管病学部的医学助理教授。S博士是预防心脏病学领域的专科医生，对血管生物学有研究兴趣。他因酒精对内皮细胞(EC)介导的纤溶作用的心脏保护作用而获得多个杰出的部门奖，并在几个国家会议上发表了他的研究成果。他的提议将确定红酒酚类化合物与EC介导的纤溶持续增加之间的关系，这可能在一定程度上有助于心脏保护。因为适量饮用红葡萄酒可以降低罹患冠心病的风险，这可能是由于酒精和葡萄酒中酚类化合物的抗氧化潜力或其他作用的共同作用。可以想象，选定的葡萄酒酚类化合物、白藜芦醇、栎素和儿茶素可能具有额外的性质，这些性质可能会影响EC的长期功能，特别是纤溶作用，而不依赖于它们直接的短期抗氧化性。进行这些初步研究是为了确定精选葡萄酒酚类物质是否确实可以诱导t-PA和/或u-PA的表达，从而显著增加EC纤溶活性的表达。葡萄酒酚诱导的表面局部EC纤溶活性增加(初步研究)可能有望降低血栓形成的风险。部分葡萄酒酚类物质将通过与PAS启动子(启动子缺失分析)(目标3)结合的因子(S)转录上调t-PA和u-PA基因表达(转录持续、转染)(目标2)，从而提高表面局部纤溶酶生成(配体结合)的催化效率(目标1)，从而在EC纤溶作用中持续长期(24小时)的增加。UAB、医学系和DCD将提供研究空间、设施、资源(秘书支持和办公空间)和适当的时间承诺(75%)，以允许候选人进行和实现本申请中规定的研究目标。在此申请期内，他将不再担任行政或教学职务。如果他的教师资助人离开学院，将任命一个新的资助人，他继续成为一名独立的医生和科学家的发展将得到支持和鼓励。

Dr. Aikens will become an Assistant Professor of Medicine on July 1, 1999, in the Division of Cardiovascular Diseases (DCD) at UAB. Dr. Aikens s subspecialty training is in the area of Preventative Cardiology with a research interest in vascular biology. He has won several distinguished departmental awards for his research cardioprotective effects of alcohol on endothelial cell(EC)-mediated fibrinolysis and has presented his research at several national meetings. His proposal will define the relationship between red wine phenolic compounds and sustained increases of EC mediated fibrinolysis, which may contribute, in part, to cardioprotection. Since the reduced risk for CAD has been attributed to moderate red wine consumption, which may be due to the combined effects of ethanol and the antioxidant potential or other effects of phenolic compounds in wine. It is conceivable that selected wine phenolic compounds, resveratrol, quercetin and catechin may have additional properties which may affect EC function in the long-term, in particular fibrinolysis, independent of their direct short-term antioxidant properties. These preliminary studies were carried out to determine whether select wine phenolics may, in fact, induce the expression of either t-PA and/or u-PA, resulting in a significant sustained increased expression of EC fibrinolytic activity. Wine phenolic-induced increased surface-localized EC fibrinolytic activity (preliminary studies) may be expected to decrease thrombotic risk. Selected wine phenolics will exert a sustained long-term (24 h) increase in EC fibrinolysis by increasing the catalytic efficiency of surface-localized plasmin generation (ligand binding) (Aim 1) resulting from the transcriptional upregulation of t-PA and u-PA gene expression(transcription run-on, transfection)(Aim 2) through factor(s) that bind to specific cis-acting regulatory region(s) in the PAs promoters(promoter deletion analysis) (Aim 3). UAB, Department of Medicine and DCD will provide the research space, facilities, resources (secretarial support and office space) and appropriate time commitment (75 percent) to allow the candidate to conduct and accomplish the research goals set forth in this application. He will have no administrative or teaching duties during the period of this application. If his faculty sponsor were to leave the institution, a new sponsor will be appointed and his continued development toward becoming an independent physician, scientist will be supported and encouraged.