A Mechanistic Study to elucidate the role of Protein S in elevating the risk of Thrombosis in Obese, Pre-menopausal women

蛋白质S(PS)是一种独特的蛋白质，因为它具有非酶抗凝剂的功能， 因为它与血浆成分相互作用，这些成分既起止血作用，又起作用 发炎。PS缺乏是最常见的高凝状态的主要原因 突出表现为深静脉血栓形成、中风和心肌梗塞。许多因素都有影响 获得性血浆PS缺乏症。其中一个因素是性激素的浓度，特别是 雌激素。在女性中，使用口服避孕药(OCA)导致的雌激素增加会导致 PS降低。重要的是，这种避孕药引起的PS减少增加了 血栓形成3倍。PS水平的降低也与肥胖有关，肥胖会增强 血栓形成的风险增加2-3倍。戏剧性地，血栓形成的风险增加了多达24- 在使用OCA的肥胖女性中加入。因为40%的美国女性人口肥胖，10%的美国女性肥胖 病态肥胖的女性中，血栓并发症是相当大的临床副作用。 在使用OCA的绝经前妇女中。 我们将确定细菌数量急剧增加的生化和分子基础。 使用OCA的肥胖女性血栓形成的发生率。具体地说，我们将回答两个重要问题 问题：(1)OCA和肥胖分别如何引起血浆PS水平的变化和(2) OCA和肥胖是如何协同增加血栓风险的。我们有初步调查结果 提示HIF1α和ERα这两个关键转录因子在肥胖中起作用。 对雌激素有反应，单独抑制PS基因的表达，而且，重要的是， 进一步协同，协同降低PS基因的表达。评估…的活动 HIF1α和ERα在不同的状态下，我们将使用体外检测，体外检测，细胞检测， 和小鼠模型，在HIF1α和ERα存在的情况下测量PS的表达。此外, 我们将测试几种方法来提高肥胖、OCA治疗的小鼠的PS水平，以降低 血栓形成的发生率。我们的研究将为设计新的治疗方法提供动力 女性人群中血栓形成的重大风险。

Protein S (PS) is a unique protein because it functions non-enzymatically as an anticoagulant, and because it interacts with plasma components that function in both hemostasis and inflammation. PS deficiency is a major cause of hypercoagulability that manifests most prominently as deep vein thrombosis, stroke and myocardial infarction. Many factors contribute to acquired plasma PS deficiency. One factor is the concentration of sex hormones, especially estrogen. In women, an increase in estrogen from use of oral contraceptives (OCA) causes a decrease in PS. Importantly, this contraceptive-induced PS decrease enhances the risk of thrombosis by 3-fold. Decreased PS levels are also associated with obesity, which enhances the risk of thrombosis by 2-3 fold. Dramatically, the risk of thrombosis increases as much as 24- fold in obese women using OCA. Because 40% of the US female population is obese and 10% of females is morbidly obese, thrombotic complications represent a sizeable clinical side effect among premenopausal women using OCA. We will determine the biochemical and molecular basis for the dramatic increase in the incidence of thrombosis in obese women using OCA. Specifically, we will answer two important questions: (1) How do OCA and obesity, individually, cause changes in plasma PS level and (2) How do OCA and obesity synergistically elevate thrombotic risk. We have preliminary findings suggesting that two key transcription factors, HIF1α, which is active in obesity, and ERα, which is responsive to estrogen, individually repress expression of the PS gene, and, importantly, cooperate to still further, synergistically reduce PS gene expression. To assess the activities of HIF1α and ERα in various states, we will use in vitro assays, ex vivo assays, cell-based assays, and mouse models to measure PS expression in the presence of HIF1α and ERα. In addition, we will test several methods to augment PS levels in obese, OCA-treated mice to reduce the incidence of thrombosis. Our studies will provide the impetus to devise novel therapies for the significant risk of thrombosis in the female population.