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.

蛋白质S（PS）是一种独特的蛋白 并且因为它与在止血和止血作用的血浆成分相互作用 炎。 PS缺乏症是表现大多数超凝性的主要原因 突出的静脉血栓形成，中风和心肌梗塞。许多因素贡献了 获得血浆PS缺乏。一个因素是性恐怖的集中度，尤其是 雌激素。在女性中，使用口服避孕药（OCA）的雌激素增加导致 减少PS。重要的是，这种避孕引起的PS降低会增强 血栓形成3倍。 PS降低也与肥胖有关，这可以增强 血栓形成2-3倍的风险。急剧上，血栓形成的风险高达24-- 使用OCA折叠肥胖的妇女。因为40％的美国女性肥胖，10％ 女性的病态肥胖，血栓形成并发症代表了相当大的临床副作用 在使用OCA的绝经前妇女中。 我们将确定急剧增加的生化和分子基础 使用OCA的肥胖妇女血栓形成的发生率。具体来说，我们将回答两个重要的 问题：（1）OCA和肥胖如何单独地导致血浆PS水平的变化和（2） OCA和肥胖如何合成升高血栓形成风险。我们有初步发现 表明在肥胖症中活跃的两个关键转录因子HIF1α和ERα，这是 对雌激素的反应敏感，单独反映PS基因的表达，重要的是 合作以进一步协同降低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，实体测定，基于细胞的测定，基于细胞的测定， 小鼠模型在HIF1α和ERα存在下测量PS表达。此外， 我们将测试几种方法以增加肥胖的OCA处理小鼠的PS水平，以减少 血栓形成的发生率。我们的研究将为设计新颖的疗法的动力 女性人群血栓形成的显着风险。