A SYSTEMS BIOLOGY APPROACH TO IDENTIFYING THE MECHANISMS OF SEX HORMONE INDUCED THROMBOEMBOLISM IN PRE-MENOPAUSAL WOMEN

确定绝经前女性性激素诱发血栓形成机制的系统生物学方法

• 批准号: 10468314
• 负责人: Jorge A Di Paola
• 金额: $ 60.83万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468314
• 关键词: Acute; Address; Adhesions; Adhesives; Affect; Agonist; Arachidonic Acids; Attenuated; Blood Platelets; Blood coagulation; Calcium; Carbon; Chronic; Collagen; Computer Models; Contraceptive methods; Data; Development; Dose; Endothelial Cells; Endothelium; Epoprostenol; Estradiol; Estrogens; Exons; Exposure to; Gene Expression; Genes; Genomics; Goals; Gonadal Steroid Hormones; Health; Hemostatic Agents; Hemostatic function; High Risk Woman; Hormone Receptor; Hormones; Hour; Incubated; Introns; Isotopes; Knowledge; Life; Maps; Measures; Megakaryocytes; Metabolic; Metabolic Marker; Metabolism; Methods; Microfluidics; Mission; Mitochondria; Modeling; Oral; Outcome; Pathway interactions; Phase; Phenotype; Physiological; Platelet Activation; Platelet aggregation; Play; Premenopause; Process; Prostaglandins I; Public Health; Reporting; Research; Risk; Role; Safety; System; Systems Biology; Systems Development; Technology; Testing; Thromboembolism; Thrombosis; Thromboxane A2; Thromboxanes; Time; United States; United States National Institutes of Health; Unsafe Sex; Whole Blood; Woman; Work; base; cardioprotection; cohort; disability; eicosanoid metabolism; experimental study; fatty acid metabolism; female sex hormone; genetic variant; genomic biomarker; hormone therapy; improved; inhibitor; innovation; insight; interest; knowledge base; men; non-genomic; novel; phenotypic biomarker; platelet function; receptor; receptor density; response; shear stress; thrombotic; tool; transcriptome sequencing; vascular injury; venous thromboembolism

Hormone therapies like oral contraception (OC) confer a heightened risk of venous thromboembolism (VTE) in premenopausal women. Until we gain mechanistic insights into why this happens, it is not possible to predict who is at risk for sex hormone-induced VTE. The long-term goal of this research is to identify the mechanisms by which sex hormones modulate hemostasis and thrombosis. The overall objective in this application is to determine how OC alter platelet function using a systems biology approach that combines –omics technologies with computational models. Previous work on hormone-induced VTE have implicated several mechanisms related to platelet function including response to agonists, metabolism of arachidonic acid (AA), and gene expression. Systematic studies of these processes over different time scales and how they relate to each other is lacking and will be addressed here. The central hypothesis is that OC increase platelet reactivity over three time scales; (i) acutely (seconds-minutes) by potentiating calcium release from intracellular stores, (ii) metabolically (minutes-hours) by elevating thromboxane metabolism, and (iii) genomically (days-months) by altering the expression of adhesive receptors. This hypothesis is based on preliminary data that platelets incubated with physiologic concentrations of 17β-estradiol have higher intracellular calcium concentrations following adhesion to collagen and altered central metabolism. The rationale for the proposed research two- fold: (i) the development of new tools to study hormone-induced VTE over multiple time scales, and (ii) to measure the effects of exogenous hormones on platelet function over these time scales. This hypothesis will be tested by two specific aims: 1) Development of systems biology tools. 2) Measuring the effects of OC on platelet function over diverse time scales. Under the first aim, computational models of calcium dynamics and metabolism in platelets will be developed informed by experiments of platelet adhesion and metabolic flux analysis. Additionally, we will perform sequencing of gene variants known to affect platelet function and hormone receptors. Finally, existing microfluidic models of vascular injury will be refined to incorporate endothelial cells to measure platelet-endothelium interactions. Under the second aim, we will use the tools developed in the first aim to measure changes in platelet function following acute and chronic exposure to exogenous hormones. These studies will include tracking platelet function in a cohort of women prior to and after starting OC. The approach is innovative because it represents a new and substantive departure from the status quo by using a systems biology approach to measure and model the influence of sex hormones on platelet function over time scales of seconds to years. The proposed research is significant, because it will identify the mechanism(s) by which exogenous sex hormone confer a pro- and/or antiplatelet phenotype in premenopausal women by both non-genomic and genomic pathways. Ultimately, such knowledge has the potential to improve the safety of hormone therapies in the United States.

激素治疗，如口服避孕药(OC)，增加了患者静脉血栓栓塞症(VTE)的风险 绝经前的女性。在我们对为什么会发生这种情况有了机械性的了解之前，是不可能预测的 谁有患性激素诱导的静脉血栓形成的风险。这项研究的长期目标是确定这些机制 性激素通过其调节止血和血栓形成。此应用程序的总体目标是 用结合组学技术的系统生物学方法确定OC如何改变血小板功能 使用计算模型。以前关于激素诱导的静脉血栓形成的研究涉及到几种机制 与血小板功能有关的包括对激动剂的反应、花生四烯酸(AA)的代谢和基因 表情。对不同时间尺度上的这些过程及其相互关系的系统研究 是欠缺的，将在这里加以解决。中心假设是OC使血小板的反应性增加超过3 时间尺度；(I)通过促进细胞内储存的钙释放而剧烈地(秒-分钟)，(Ii) 通过提高血栓素代谢来代谢(分钟-小时)，以及(Iii)在基因组上(天-月) 改变黏附受体的表达。这一假设是基于初步数据，即血小板 与生理浓度的17β-雌二醇孵育后，细胞内钙离子浓度较高 与胶原蛋白粘连后，中枢代谢发生改变。拟议研究的理由有两点： 折叠：(I)开发新的工具来研究多个时间尺度上的激素诱导的静脉血栓栓塞，以及(Ii) 在这些时间尺度上测量外源性激素对血小板功能的影响。这一假说将 通过两个具体目标进行测试：1)开发系统生物学工具。2)测量OC对以下各项的影响 不同时间段的血小板功能。在第一个目标下，钙动力学和钙动力学计算模型 通过对血小板黏附和代谢通量的实验了解到血小板中的新陈代谢。 分析。此外，我们还将对已知的影响血小板功能和 荷尔蒙受体。最后，现有的血管损伤的微流体模型将被改进，以纳入 内皮细胞测量血小板与内皮细胞的相互作用。在第二个目标下，我们将使用工具 开发的第一个目的是测量急性和慢性暴露后血小板功能的变化 外源激素。这些研究将包括跟踪一组女性在治疗前和治疗前的血小板功能。 在启动OC之后。这种方法是创新的，因为它代表了对 通过使用系统生物学方法来测量和模拟性激素对 从几秒到几年的时间范围内，血小板的功能。这项拟议的研究意义重大，因为它将 确定外源性性激素在糖尿病大鼠体内产生促血小板和/或抗血小板表型的机制(S) 非基因组途径和基因组途径对绝经前妇女的影响。归根结底，这种知识具有 在美国提高激素疗法安全性的潜力。