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：
10640874
负责人：
JORDAN A SHAVIT
金额：
$ 51.49万
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/10640874
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 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&apos s Health Zebrafish candidate identification 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

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.

项目摘要/摘要妇女一生都暴露于性激素，使她们处于更高的风险心血管疾病通常是病理性凝结（静脉血栓形成/血栓栓塞），并且导致明显的发病率和死亡率。由于性别和性别而过度暴露于雌激素通过月经，内分泌疾病和外源补充避孕，激素替代和性别过渡。尽管众所周知，性激素会诱导许多凝血因子，将雌激素连接到凝血系统的途径和机制就像为什么要对血栓形成进展一样，人们对此很了解。这些调解人的识别是对潜在的病理生理学的任何全面了解，都可以帮助确定较高的患者血栓形成的风险，也可能会确定未来的治疗靶标。知识的原因之一差距是缺乏发展雌激素引起的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，以识别将性激素与血栓栓塞。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。在初步研究，我们证明了斑马鱼中凝血系统的广泛保护胚胎和幼虫中血栓形成的性激素诱导，包括荧光标记和容易可见的雌激素诱导的纤维蛋白血栓。这些研究将确定介导联系的关键蛋白质在性激素和凝血因子之间。这将导致候选小组的快速发展将增强我们对性激素诱导的血栓形成的理解的因素，并有可能允许 AT风险患者的分层。鉴定出的新基因还将产生潜在的治疗靶标，并且预防策略，并将为未来的翻译研究提供信息。使用小分子的途径分析将还可以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。这些研究将为性别和性别对疾病的影响提供见解，并与许多战略目标中的目标1 2019 - 2023年跨NIH妇女健康研究战略计划，包括研究特别影响心血管，月经和妇科的条件妇女的健康。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CRISPR/Cas9-Mediated Genome Editing in Zebrafish.

CRISPR/Cas9 介导的斑马鱼基因组编辑。

DOI：
10.1007/978-1-0716-2990-1_17
发表时间：
2023
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Daniel,JeffreyG;Yu,Xinge;Ferguson,AllisonC;Shavit,JordanA
通讯作者：
Shavit,JordanA

Nuclear Progestin Receptor-mediated Linkage of Blood Coagulation and Ovulation.

核孕激素受体介导的凝血和排卵的联系。

DOI：
10.1210/endocr/bqac057
发表时间：
2022
期刊：
Endocrinology
影响因子：
4.8
作者：
Huang,Jing;Sun,Chao;TengLiu,Dong;Zhao,NanNan;Shavit,JordanA;Zhu,Yong;Chen,ShiXi
通讯作者：
Chen,ShiXi