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

基本信息

批准号：
10062572
负责人：
JORDAN A SHAVIT
金额：
$ 54.6万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10062572
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 Preventive Intervention 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&apos 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 public health relevance sex small molecule small molecule libraries therapeutic target transcriptome sequencing transgender women translational study whole genome

项目摘要

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.

项目概要/摘要女性一生都会接触性激素，这使她们面临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），以及导致显着的发病率和死亡率。由于性行为和性别而发生过多接触雌激素月经、内分泌失调、外源性补充避孕、激素更替和性别转变。尽管众所周知，性激素会诱导多种性激素的表达。凝血因子，连接雌激素与凝血系统的途径和机制，以及至于为什么会进展为血栓形成，人们知之甚少。识别这些介体对于对潜在病理生理学的任何全面了解，都可以帮助确定患者处于更高的水平血栓形成的风险，也可能确定未来的治疗目标。知识的原因之一差距是缺乏发展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可识别性激素与血栓栓塞。该项目将利用高度创新的技术，包括基因组编辑斑马鱼模型中的核酸酶、下一代测序和小分子分析。在初步研究，我们已经证明斑马鱼的凝血系统得到广泛保护胚胎和幼虫中血栓形成的性激素诱导，包括荧光标记和易标记的可见雌激素诱导的纤维蛋白血栓。这些研究将确定介导这种联系的关键蛋白质性激素和凝血因子之间。这将导致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，并可能使对高危患者进行分层。鉴定出的新基因也将产生潜在的治疗靶点和预防策略，并将为未来的转化研究提供信息。使用小分子的通路分析将还确定了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。这些研究将深入了解性和性别对疾病的影响，并与许多研究相一致 2019-2023 年跨 NIH 女性健康研究战略计划战略目标 1 中的目标，包括对特别影响心血管、月经和妇科疾病的调查妇女的健康。