Model system of oral contraceptive-induced VTE: integrating genomic, transcriptomic, and proteomic discovery with functional biology

口服避孕药诱发的 VTE 模型系统：将基因组学、转录组学和蛋白质组学发现与功能生物学相结合

• 批准号: 10164668
• 负责人: CHARLES J LOWENSTEIN
• 金额: $ 67.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-25 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164668
• 关键词: Affect; Biochemistry; Biological; Biological Models; Biology; Blood; Candidate Disease Gene; Case-Control Studies; Cells; Cellular biology; Clinical; Coagulation Process; Contraceptive Usage; Data; Development; Endothelial Cells; Endothelium; Environmental Risk Factor; Epidemiologist; Epidemiology; Event; Gene Proteins; Genes; Genetic; Genomics; Goals; Hormones; Human; In Vitro; Inherited; Lead; Link; Methods; Modeling; Molecular; Oral Contraceptives; Pathway interactions; Phase; Plasma; Population; Population Biology; Premenopause; Proteins; Proteomics; Provider; Resources; Risk; Risk Factors; Signal Transduction; Source; Techniques; Testing; Thrombophilia; Thrombosis; Thrombus; Triad Acrylic Resin; Validation; Variant; Woman; Women' s Health; Work; base; clinically significant; endothelial cell procoagulant activity; female sex hormone; genetic risk factor; genetic variant; genomic data; genomic locus; high risk; in vitro Model; novel; novel strategies; novel therapeutics; prevent; protein biomarkers; response; tool; transcriptomics; venous thromboembolism; young woman

Venous thromboembolism (VTE) is caused by a combination of blood hypercoagulability, endothelial dysregulation, and blood stasis. This biologic dysregulation has environmental and inherited sources that interact to modulate thrombotic risk. Female sex-hormone-based oral contraceptives (OCs) are an important environmental cause of thrombosis in young women, increasing the risk of VTE 2 to 4-fold. The aim of this application is to elucidate mechanisms by which exogenous female sex hormones (OCs) increase the risk of VTE in premenopausal women. Our proposal has 4 aims, which will drive biologic discovery and functional experimentation. R61 Overview: Discovery. In the first 2 years of this proposal, we proposed to identify new genes, protein markers, and biologic pathways associated with OC use and VTE risk using “panomic” resources (genomic, transcriptomic, and proteomic) and functional cell biology and biochemistry techniques. Aim 1: Identify novel genes that contribute to VTE in premenopausal women using OCs in 3 well- characterized, case-control studies of VTE. We have accomplished this Aim. Aim 2: Characterize effects of OCs on endothelial cell (EC) transcriptomic and proteomic responses, EC procoagulant activity, and ability to promote clot formation. We have accomplished this Aim. R33 Overview: Validation and Functional Testing. In the next 3 years of this proposal, we will validate candidate genes and proteins identified in the R61 phase, characterizing their function in an in vitro cell-based model of coagulation. We will characterize interactions between EC dysregulation and plasma hypercoagulability to promote the formation of prothrombotic clots in a blood-endothelial interface model. Aim 3: Characterize candidate genes and proteins in human populations, focusing on Aim 2 discoveries. Aim 4: Characterize the novel candidate genes identified through discovery and validation in the aims above, and determine effects of each gene on EC procoagulant activity in normal and hypercoagulable plasmas. Collectively, these aims integrate discovery and functional-analysis information to identify biologic variation that promotes OC-induced VTE. This study will yield functionally-validated molecular signals and a blood-endothelial interface model for incorporation into VTE risk prediction tools in premenopausal women.

静脉血栓栓塞（VTE）是由血液高凝性（内皮）组合引起的 失调和血液暂停。这种生物失调具有环境和继承的来源 相互作用以调节血小板风险。基于女性性激素的口服避孕药（OC）是重要的 年轻女性血栓形成的环境原因，增加了VTE 2至4倍的风险。这个目的 应用是阐明外源性女性性激素（OC）增加的机制 vte在绝经前妇女中。我们的建议有4个目标，这将推动生物学发现和功能性 实验。 R61概述：发现。在该提案的前两年中，我们建议确定新的 与OC使用和VTE风险相关的基因，蛋白质标志物和生物学途径使用“ panomic” 资源（基因组，转录组和蛋白质组学）以及功能细胞生物学和生物化学技术。 AIM 1：确定使用3个良好的OCS的新型基因，这些基因有助于VETE的VTE 表征了VTE的病例对照研究。我们已经实现了这个目标。目标2：表征 内皮细胞（EC）转录组和蛋白质组学反应的OCS，EC凝聚活性以及能够 促进凝块形成。我们已经实现了这个目标。 R33概述：验证和功能测试。 在本提案的接下来的三年中，我们将验证在R61期确定的候选基因和蛋白质， 在基于体外​​细胞的凝结模型中表征其功能。我们将表征互动 在EC失调和血浆高凝性之间，以促进A 血内皮接口模型。 AIM 3：在人类种群中表征候选基因和蛋白质， 专注于目标2发现。目标4：特征通过发现和 在上述目的中进行验证，并确定每个基因对正常和 超凝等离子体。这些目标是集成发现和功能分析信息 确定促进OC诱导的VTE的生物变异。这项研究将产生功能验证的分子 公司的信号和血端界面模型在VTE风险预测工具中 绝经前妇女。