Dissection of the mechanisms underlying sex-influenced cardiovascular disease

剖析性别影响的心血管疾病的潜在机制

• 批准号: 10407073
• 负责人: JORDAN A SHAVIT
• 金额: $ 52.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407073
• 关键词: ATAC-seq; Affect; Animal Model; Area; Basic Science; Biological Models; Biology; Blood Coagulation Factor; Cardiovascular Diseases; Cardiovascular system; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Coagulation Process; Contraceptive methods; Data; Development; Disease; Dissection; Embryo; Endocrine System Diseases; Endothelial Cells; Environment; Environmental Exposure; Equilibrium; Estrogens; Ethylnitrosourea; Evaluation; Event; Exposure to; FDA approved; Fertilization; Fibrin; Fibrinogen; Functional disorder; Future; Gender; Genes; Genetic; Genetic Transcription; Goals; Gonadal Steroid Hormones; Gynecologic; Hemorrhage; Hemostatic Agents; Hepatocyte; Hormonal; Hormone Receptor; Hormones; Human; Individual; Intake; Investigation; Knowledge; Larva; Lead; Light; Link; Maps; Mediating; Mediator of activation protein; Menstruation; Menstruation Disturbances; Microscopy; Modeling; Morbidity - disease rate; Mutagenesis; Nitrosourea Compounds; Optics; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Prevention strategy; Proteins; Reagent; Research; Risk; Signal Transduction; Strategic Planning; Stratification; Supplementation; System; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Thromboembolism; Thrombosis; Thrombus; Tissues; Transcriptional Regulation; Transgenic Organisms; United States National Institutes of Health; Venous Thrombosis; Woman; Women' s Health; Zebrafish; base; cardiovascular disorder risk; estrogenic; experience; experimental study; gender transition; gene discovery; genome editing; genome sequencing; genome-wide; girls; high risk; innovative technologies; insight; mortality; mutant; new therapeutic target; next generation sequencing; novel; novel diagnostics; novel therapeutics; nuclease; offspring; prevent; preventive intervention; public health relevance; sex; small molecule; small molecule libraries; therapeutic target; thrombotic; transcriptome sequencing; transgender women; translational study; whole genome

PROJECT SUMMARY/ABSTRACT Women are exposed to sex hormones throughout their lifetimes, putting them at significantly higher risk for cardiovascular disease which is typically pathologic clotting (venous thrombosis/thromboembolism), and resulting in significant morbidity and mortality. Excessive exposure to estrogens due to sex and gender occurs with menstruation, endocrine disorders, and exogenous supplementation for contraception, hormone replacement, and gender transition. Although it is known that sex hormones induce expression of a number of coagulation factors, the pathways and mechanisms that connect estrogen to the coagulation system, as well as why there is progression to thrombosis, is poorly understood. Identification of these mediators are central to any comprehensive understanding of the underlying pathophysiology, could help ascertain patients at higher risk for thrombosis, and might also pinpoint future therapeutic targets. One of the reasons for the knowledge gap is the lack of an animal model that develops estrogen-induced thrombosis. We propose to exploit the powerful genetics of the zebrafish model system to identify the pathways that connect sex hormones to thromboembolism. This project will leverage highly innovative technologies, including genome editing nucleases, next generation sequencing, and small molecule analysis in the context of the zebrafish model. In preliminary studies, we have demonstrated widespread conservation of the coagulation system in zebrafish and sex hormone induction of thrombosis in embryos and larvae, including fluorescently-tagged and easily visible estrogen-induced fibrin thrombi. These studies will identify the critical proteins that mediate the link between sex hormones and coagulation factors. This will result in the rapid development of a candidate panel of factors that will enhance our understanding of sex hormone-induced thrombosis, and potentially allow stratification of at risk patients. Novel genes identified will also yield potential therapeutic targets and preventative strategies, and will inform future translational studies. Pathway analysis using small molecules will also identify potential therapeutic compounds that might treat or prevent estrogen-induced thrombosis. These studies will provide insights into the effects of sex and gender on disease, and are aligned with a number of the objectives in Strategic Goal 1 of the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research, including investigation of conditions that specifically affect the cardiovascular, menstrual, and gynecologic health of women.

项目摘要/摘要 女性在一生中都会接触到性激素，这使她们面临着显著更高的风险。 心血管疾病，通常是病理性凝血(静脉血栓形成/血栓栓塞症)，以及 导致严重的发病率和死亡率。因性行为和性别而过度接触雌激素的情况发生 月经、内分泌紊乱和外源性避孕、激素补充 更替和性别转变。尽管已知性激素可诱导多种基因表达 凝血因子，连接雌激素和凝血系统的途径和机制 至于为什么会进展为血栓形成，人们知之甚少。确定这些调解人是关键 任何对潜在病理生理学的全面了解，都可以帮助确定患者处于更高的 有血栓形成的风险，也可能确定未来的治疗目标。了解这一信息的原因之一 GAP是缺乏雌激素诱导血栓形成的动物模型。我们建议利用 斑马鱼模型系统的强大遗传学，以确定将性激素与 血栓栓塞症。该项目将利用高度创新的技术，包括基因组编辑 在斑马鱼模型的背景下，核酸酶、下一代测序和小分子分析。在……里面 初步研究表明，斑马鱼的凝血系统广泛保守。 和性激素诱导胚胎和幼虫血栓形成，包括荧光标记的和容易的 可见雌激素诱导的纤维蛋白血栓。这些研究将确定调节这种联系的关键蛋白质。 性激素和凝血因子之间的关系。这将导致一个候选小组的快速发展 这些因素将增强我们对性激素诱导的血栓形成的理解，并有可能使 高危患者的分层。已发现的新基因也将产生潜在的治疗靶点和 预防性策略，并将为未来的翻译研究提供信息。使用小分子进行通路分析将 还要确定可能治疗或预防雌激素诱导的血栓形成的潜在治疗化合物。这些 研究将提供对性和性别对疾病的影响的见解，并与许多 《2019-2023年跨NIH妇女健康研究战略计划》战略目标1中的目标， 包括调查对心血管、月经和妇科有特殊影响的疾病 妇女的健康。