Impact of disruptions in the serotonin system on cardiac development

血清素系统破坏对心脏发育的影响

• 批准号: 9883833
• 负责人: Sarah Elizabeth Haskell
• 金额: $ 16.06万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883833
• 关键词: Acute; Affect; Americas; Antidepressive Agents; Basic Science; Biological; Biological Assay; Biology; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Physiology; Cardiovascular system; Child; Childhood; Clinical Research; Congenital Heart Defects; Consumption; Counseling; Critical Care; Data; Development; Development Plans; Developmental Biology; Embryo; Environment; Exhibits; Exposure to; Faculty; Fetal Development; Fetal Heart; Fetus; Genes; Genetic; Genetic Epistasis; Genetic Models; Goals; Heart; Heart Abnormalities; Heart Diseases; Investigation; K-Series Research Career Programs; Knockout Mice; Knowledge; Laboratories; Link; Mammals; Mediating; Mentors; Methods; Modeling; Molecular; Mus; Organizational Models; Pathogenesis; Pharmaceutical Preparations; Pharmacology; Physicians; Placenta; Play; Pregnancy; Pregnant Women; Prevention; Process; Program Development; Publishing; Regulation; Research; Research Personnel; Risk; Rodent; Role; Scientist; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2B; Sertraline; Shapes; Signal Pathway; Signal Transduction; Study models; Systems Development; Techniques; Testing; Time; Training; United States; Work; Zebrafish; base; cardiogenesis; career; career development; cell type; congenital heart disorder; design; developmental genetics; epidemiologic data; expectation; experience; extracellular; fetal; fetal programming; genetic manipulation; genome editing; heart visualization; insight; knock-down; maternal depression; migration; mutant; offspring; prevent; reuptake; serotonin transporter; skills; treatment optimization

ABSTRACT This proposal describes a three-year mentored career development program designed to prepare Dr. Sarah Haskell for her long-term career goal of being an independent, clinician-scientist focused on furthering our understanding of acquired heart defects. This proposal builds on Dr. Haskell's background as a pediatric critical care physician and a basic scientist with significant experience in fetal programming and cardiovascular physiology by providing rigorous training in developmental biology and genetics. Dr. Haskell has established a mentoring team with expertise in cardiovascular research, developmental biology, and genetic regulation of heart development and cellular differentiation. This work will be supported in an outstanding environment rich in cardiovascular research with years of experience mentoring young faculty. Serotonin (5-HT) plays an important role in normal heart development and heart defects have been linked to selective serotonin reuptake inhibitors (SSRIs). SSRIs work by inhibiting the serotonin transporter (SERT), thus impacting 5-HT signaling. The proposal builds on Dr. Haskell's preliminary data in zebrafish embryos showing both exposure to sertraline, the most commonly prescribed SSRI, and application of a 5-HT2B receptor (htr2b) morpholino cause abnormalities in heart development. With 10% of pregnant women in the United States taking SSRIs during pregnancy, these investigations are not only timely but critical to properly counsel expectant mothers. The overall goal of the proposal is to determine the impact of disruptions in the 5-HT system on cardiac development. We will be able to capitalize on strengths of the zebrafish model for studying cardiac development and investigate specific gene, cell type, and signaling pathways to determine the mechanism of abnormal heart development. Dr. Haskell will first test the hypothesis that sertraline affects heart development by regulating SERT function. Using both morphants and mutants, she will characterize the cardiac defects in SERT-deficient zebrafish embryos by evaluating critical steps in heart development including migration, cardiac looping, and formation of the second heart field and atrioventricular canal. Dr. Haskell will further test her hypothesis that disruption of the 5-HT system leads to developmental heart defects through the 5-HT2B receptor. She will test her hypothesis that the 5- HT2B receptor regulates heart development via the Gq/11 signaling pathway. Finally, Dr. Haskell will perform an epistasis assay to determine if SSRIs act via SERT and/or the 5- HT2B receptor to impact cardiac development. Understanding the mechanisms responsible for adaptive and maladaptive cardiac development will enhance our knowledge of cardiovascular biology with broader implications for children with heart disease.

抽象的 该提案描述了一项为期三年的指导职业发展计划，旨在帮助莎拉博士做好准备 哈斯克尔的长期职业目标是成为一名独立的临床医生科学家，专注于进一步发展我们的 了解获得性心脏缺陷。该提案建立在哈斯克尔博士作为儿科医师的背景之上 重症监护医师和基础科学家，在胎儿编程和心血管方面拥有丰富的经验 通过提供发育生物学和遗传学方面的严格培训来学习生理学。哈斯克尔博士建立了一个 具有心血管研究、发育生物学和遗传调控专业知识的指导团队 心脏发育和细胞分化。这项工作将得到良好的环境和丰富的支持 从事心血管研究，拥有多年指导年轻教师的经验。血清素 (5-HT) 具有 在正常心脏发育和心脏缺陷中发挥重要作用，与选择性血清素再摄取有关 抑制剂（SSRIs）。 SSRIs 通过抑制血清素转运蛋白 (SERT) 发挥作用，从而影响 5-HT 信号传导。 该提案建立在哈斯克尔博士在斑马鱼胚胎中的初步数据的基础上，这些数据显示暴露于 舍曲林（最常用的 SSRI）和 5-HT2B 受体 (htr2b) 吗啉的应用 心脏发育异常。 10% 的美国孕妇在怀孕期间服用 SSRIs 怀孕期间，这些检查不仅及时，而且对于为准妈妈提供适当的咨询至关重要。这 该提案的总体目标是确定 5-HT 系统中断对心脏的影响 发展。我们将能够利用斑马鱼模型的优势来研究心脏 开发并研究特定基因、细胞类型和信号通路以确定其机制 心脏发育异常。哈斯克尔博士将首先检验舍曲林影响心脏发育的假设 通过调节SERT功能。她将使用变形体和突变体来描述心脏缺陷的特征 通过评估心脏发育的关键步骤（包括迁移）来评估 SERT 缺陷的斑马鱼胚胎， 心脏循环，以及第二心区和房室管的形成。 Haskell博士将进一步测试 她的假设是，5-HT 系统的破坏会通过 5-HT2B 导致发育性心脏缺陷 受体。她将验证她的假设，即 5-HT2B 受体通过 Gq/11 调节心脏发育 信号通路。最后，Haskell 博士将进行上位性测定，以确定 SSRI 是否通过 SERT 发挥作用 和/或 5-HT2B 受体影响心脏发育。了解负责的机制 适应性和适应不良的心脏发育将增强我们对心血管生物学的了解 对患有心脏病的儿童具有更广泛的影响。