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

一项机制研究旨在阐明 Protein S 在增加肥胖绝经前女性血栓形成风险中的作用

• 批准号: 10544154
• 负责人: Rinku Majumder
• 金额: $ 62.08万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544154
• 关键词: Affect; Anticoagulants; Binding; Binding Proteins; Biochemical; Biological Assay; Blood flow; C57BL/6 Mouse; Cells; ChIP-on-chip; Chronic; Clinical; Coagulation Process; Collection; Contraceptive Agents; Data; Deep Vein Thrombosis; Epigenetic Process; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Factor IXa; Female; Gene Expression; Gene Proteins; Gene Targeting; Generations; Genetic Transcription; Gonadal Steroid Hormones; HIF1A gene; Hemostatic function; HepG2; Hormones; Human; Hypoxia; Incidence; Individual; Inflammation; Knowledge; Liver; Measurement; Measures; Mediating; Methods; Molecular; Morbid Obesity; Mus; Myocardial Infarction; Nucleotides; Obese Mice; Obesity; Oral Contraceptives; Plasma; Plasma Proteins; Polycythemia; Population; Predisposition; Pregnant Women; Premenopause; Progesterone; Progestins; Protein S; Protein S Deficiency; Proteins; RNA; Regulation; Regulator Genes; Reporting; Repression; Risk; Role; Sampling; Site; Stroke; Supplementation; Testing; Thrombin; Thrombophilia; Thrombosis; Thrombus; Time; Venous Thrombosis; Woman; analog; aptamer; biobank; chromatin immunoprecipitation; cohort; estrogenic; experience; gene repression; genetic regulatory protein; hypoxia inducible factor 1; in vitro Assay; inhibitor; mouse model; novel therapeutics; obese person; overexpression; promoter; protein expression; response; side effect; synergism; thrombotic; thrombotic complications; tool; transcription factor

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.

Protein S (PS) 是一种独特的蛋白质，因为它以非酶促方式发挥抗凝剂的作用， 因为它与具有止血和止血作用的血浆成分相互作用 炎。 PS 缺乏是高凝状态的主要原因，最常见的是 主要表现为深静脉血栓、中风和心肌梗塞。许多因素促成 获得性血浆 PS 缺乏症。因素之一是性激素的浓度，尤其是 雌激素。对于女性来说，使用口服避孕药（OCA）导致雌激素增加，导致 PS减少。重要的是，这种避孕引起的 PS 降低会增加以下风险： 血栓形成3倍。 PS 水平降低也与肥胖有关，从而增强 血栓形成的风险增加2-3倍。显着地，血栓形成的风险增加多达 24- 使用 OCA 对肥胖女性进行折叠。因为 40% 的美国女性肥胖，10% 女性病态肥胖，血栓并发症代表相当大的临床副作用 使用 OCA 的绝经前妇女。 我们将确定其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。具体来说，我们将回答两个重要的问题 问题：(1) OCA 和肥胖如何单独引起血浆 PS 水平的变化以及 (2) OCA 和肥胖如何协同提高血栓形成风险。我们有初步调查结果 表明两个关键的转录因子：HIF1α（在肥胖中活跃）和 ERα（在肥胖中发挥作用） 对雌激素有反应，单独抑制 PS 基因的表达，而且重要的是， 合作进一步协同减少 PS 基因表达。评估活动 HIF1α和ERα在各种状态下，我们将使用体外测定、离体测定、基于细胞的测定、 和小鼠模型来测量 HIF1α 和 ERα 存在下的 PS 表达。此外， 我们将测试几种方法来提高肥胖、OCA 治疗小鼠的 PS 水平，以减少 血栓形成的发生率。我们的研究将为设计新疗法提供动力 女性人群存在血栓形成的显着风险。