ESTROGENS AND PROGESTINS EFFECTS ON ATHEROGENESIS

本申请中提出的培训和研究将得到赞助。 由亚当斯博士撰写，并将在动脉硬化研究中发表 中心和比较医学临床研究中心。Dr。 瓦格纳正在寻求SERCA的支持，以进一步发展她作为 特别强调心血管健康的独立调查员 上了年纪的女性。这些研究将利用一种具有良好特性的灵长类动物 模特，雌性食蟹猴，在大多数西方国家喜欢女人 社会，发展不那么严重的动脉粥样硬化性冠心病 (CHD)高于男性。黄褐斑的致病机制 由于动脉粥样硬化，女性很难研究动脉粥样硬化的形成 在许多年的时间里发展缓慢。此外，虽然CHD是 美国妇女发病率和死亡率的主要原因，临床 事件发生的频率相对较低。出于这些原因，我们建议 利用灵长类动物模型来研究性激素缺乏的影响， 性激素替代及口服避孕药治疗高血压病患者 动脉粥样硬化的发病机制。 对人类和非人类灵长类动物的研究发现，只有 雌激素的有益作用的一部分可以归因于 血浆脂蛋白危险变量的变化。这表明 雌激素可能通过相互作用延缓动脉粥样硬化的形成。 动脉壁或通过改变血浆成分 脂蛋白。提出的研究将探索分子和细胞 雌激素和孕激素可能起作用的机制。其影响 将研究性激素对以下参数的影响：1) 早期动脉粥样硬化形成的功能参数，如内皮细胞 由动脉低密度脂蛋白摄取和降解决定的功能障碍， 单核细胞与内皮细胞的黏附与内膜细胞增殖，2) 全身和肝脏LSL代谢，3)血浆高密度脂蛋白的组成及其 在胆固醇逆向转运中的作用，4)细胞因子的表达 和生长因子通过动脉细胞，以及5)动脉硬化相关 血管反应受损。如果如所怀疑的那样，有益的效果 这将为预防或预防提供合理的依据 这些激素在冠心病中的治疗应用。

The training and research proposed in this application will be sponsored by Dr. Adams and will take place in both the Arteriosclerosis Research Center and the Comparative Medicine Clinical Research Center. Dr. Wagner is seeking SERCA support to further her development as an independent investigator with special emphasis on cardiovascular health of aging females. The studies will utilize a well characterized primate model, the female cynomolgus monkey, which like women in most Western societies, develops less severe atherosclerotic coronary heart disease (CHD) than its male counterpart. Pathogenetic mechanisms of atherogenesis are difficult to study in women, since atherosclerosis develops slowly over a period of many years. Also, while CHD is the leading cause of morbidity and mortality in American women, clinical events occur relatively infrequently. For these reasons we propose to utilize a primate model to study the effect of sex hormone deficiency, sex hormone replacement and oral contraceptive treatment on the pathogenesis of atherosclerosis. Studies of both human and nonhuman primates have found that only a portion of the beneficial effects of estrogens can be attributed to changes in plasma lipoprotein risk variables. This suggests that estrogens may retard atherogenesis by interacting by either directly at the arterial wall or by modifying plasma components in addition to lipoproteins. The studies proposed will explore molecular and cellular mechanisms by which estrogens and progestins may be acting. The effects of sex steroids on the following parameters will be investigated: 1) functional parameters of early atherogenesis eg., endothelial dysfunction as determined by arterial LDL uptake and degradation, monocyte adhesion to the endothelium, and intimal cell proliferation, 2) whole body and hepatic LSL metabolism, 3) plasma HDL composition and its function in reverse cholesterol transport, 4) expression of cytokines and growth factors by arterial cells, and 5) atherosclerosis-related impairment of vascular responses. If, as suspected, beneficial effects are found, this would provide a rational basis for the prophylactic or therapeutic use of these steroids in CHD.