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: 10418628
• 负责人: CHARLES J LOWENSTEIN
• 金额: $ 62.68万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418628
• 关键词: Affect; Biochemistry; Biological; Biological Models; Biology; Blood; Blood Vessels; Candidate Disease Gene; Case-Control Studies; Cells; Cellular biology; Clinical; Coagulation Process; Complex; Contraceptive Usage; Data; Development; Endothelial Cells; Endothelium; Environmental Risk Factor; Epidemiologist; Epidemiology; Event; Gene Proteins; Genes; Genetic; Genomics; Goals; Hormones; Human; In Vitro; Individual; Inherited; Lead; Methods; Modeling; Molecular; Oral Contraceptives; Pathway interactions; Phase; Phenotype; Plasma; Population; Population Biology; Premenopause; Proteins; Proteomics; Provider; Resources; Risk; Risk Factors; Signal Transduction; Source; Techniques; Technology; Testing; Thrombophilia; Thrombosis; Thrombus; Triad Acrylic Resin; Validation; Variant; Woman; Women' s Health; base; clinically significant; endothelial cell procoagulant activity; female sex hormone; genetic risk factor; genomic data; genomic locus; high risk; in vitro Model; novel; novel strategies; novel therapeutics; prevent; protein biomarkers; response; risk prediction; risk prediction model; thrombotic; 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. Ultimately, a pre- menopausal woman’s risk of VTE is multifactorial: no single inherited or environmental factor satisfactorily explains why some women who use OCs are at greater risk of a thrombotic event than others who use OCs. Assessing thrombotic risk in women before initiating OC use can help identify women who may be at higher risk of a clinical event. A risk-prediction model should account for the diverse and unique biology of each woman and how it responds to the challenge of OC hormones. The aim of this application is to elucidate mechanisms by which exogenous female sex hormones (OCs) increase the risk of VTE in premenopausal women. Over the course of the 2-phase project, we will develop and expand a model system that accounts for individual-specific and hormone-specific variables and that can be used to predict risk of thrombosis in women using OCs. Our approach is to use panomics technology to discover biology relevant to VTE in premenopausal women using OCs, and to apply panomics findings to understand the functional effects of OCs on vascular cells and blood composition. Our proposal has 4 aims, which will drive biologic discovery and functional experimentation. R61 Overview: Discovery. We will 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. Aim 2: Characterize effects of OCs on endothelial cell (EC) transcriptomic and proteomic responses, EC procoagulant activity, and ability to promote clot formation. R33 Overview: Validation and Functional Testing. 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、内皮细胞和血管内皮细胞等因素共同引起的