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

基本信息

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
项目类别：
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

项目摘要

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 PS 缺乏是导致高凝状态的主要原因。深静脉血栓、中风和心肌梗死等多种因素都有影响。导致获得性血浆 PS 缺乏的因素之一是性激素的浓度，尤其是性激素的浓度。对于女性来说，使用口服避孕药 (OCA) 会导致雌激素增加。重要的是，避孕引起的 PS 降低会增加患此病的风险。血栓形成增加 3 倍。 PS 水平降低也与肥胖有关，肥胖会增强血栓形成的风险显着增加 2-3 倍。使用 OCA 的肥胖女性比例增加，因为 40% 的美国女性肥胖，10% 的女性肥胖。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。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？我们有初步发现。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，合作进一步协同降低 PS 基因表达，以评估 PS 基因的活性。 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。我们将测试几种方法来提高肥胖、OCA 治疗小鼠的 PS 水平，以减少我们的研究将为开发新的治疗方法提供动力。女性人群存在血栓形成的显着风险。