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: 10327324
• 负责人: Rinku Majumder
• 金额: $ 64.54万
• 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/10327324
• 关键词: Address; Affect; Anticoagulants; Binding; 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 Targeting; Generations; Genes; Genetic Transcription; Gonadal Steroid Hormones; 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; Polycythemia; Population; Predisposition; Pregnant Women; Premenopause; Progesterone; Progestins; Protein S; Proteins; RNA; Regulation; Regulator Genes; Reporting; Risk; Role; Sampling; Site; Stroke; Supplementation; Testing; Thrombin; Thrombophilia; Thrombosis; Thrombus; Time; Venous Thrombosis; Woman; analog; aptamer; base; biobank; chromatin immunoprecipitation; cohort; estrogenic; experience; gene repression; genetic regulatory protein; hypoxia inducible factor 1; in vitro Assay; inhibitor; liver hypoxia; mouse model; novel therapeutics; obese person; overexpression; promoter; 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S（PS）是一种独特的蛋白质，因为它非酶促地起抗凝剂的作用， 并且因为它与在止血和止血中起作用的血浆组分相互作用， 炎症PS缺乏是高凝状态的主要原因， 突出表现为深静脉血栓形成、中风和心肌梗死。许多因素促成了 获得性血浆PS缺乏症一个因素是性激素的浓度， 雌激素.在女性中，使用口服避孕药（OCA）导致雌激素增加， PS的下降。重要的是，这种避孕引起的PS降低增加了 血栓形成3倍。PS水平降低也与肥胖有关，这增强了 血栓形成的风险降低2-3倍。令人惊讶的是，血栓形成的风险增加多达24- 使用OCA的肥胖女性中增加了10%。因为40%的美国女性人口肥胖， 的女性为病态肥胖，血栓性并发症代表了相当大的临床副作用 使用OCA的绝经前妇女。 我们将确定的生物化学和分子基础的急剧增加， 使用OCA评估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;（2） OCA和肥胖如何协同增加血栓形成风险。我们有初步的调查结果 提示两个关键的转录因子，HIF 1 α，在肥胖中活跃，ERα， 对雌激素有反应，单独抑制PS基因的表达，重要的是， 进一步协同降低PS基因表达。评估的活动 HIF 1 α和ERα在各种状态下，我们将使用体外试验，离体试验，基于细胞的试验， 和小鼠模型来测量在HIF 1 α和ERα存在下的PS表达。此外，本发明还提供了一种方法， 我们将测试几种方法来增加肥胖的、经OCA治疗的小鼠的PS水平， 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显著风险。