Impact of disruptions in the serotonin system on cardiac development

摘要 这份提案描述了一个为期三年的有指导的职业发展计划，旨在为萨拉博士做好准备 哈斯克尔的长期职业目标是成为一名独立的临床医生兼科学家，专注于推动我们的 了解获得性心脏缺陷。这项建议是建立在哈斯克尔医生作为儿科医生的背景之上的 重症监护医生和一位在胎儿规划和心血管方面有丰富经验的基础科学家 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。哈斯克尔博士已经建立了一种 具有心血管研究、发育生物学和遗传调控方面的专业知识的指导团队 心脏发育和细胞分化。这项工作将在一个出色的丰富环境中得到支持 从事心血管研究，有多年指导年轻教员的经验。5-羟色胺(5-羟色胺)在 在正常心脏发育和心脏缺陷中的重要作用与选择性5-羟色胺再摄取有关 抑制剂(SSRI)。SSRI通过抑制5-羟色胺转运体(SERT)发挥作用，从而影响5-羟色胺信号转导。 该建议建立在哈斯克尔博士在斑马鱼胚胎上的初步数据基础上，这些数据显示，两种环境都暴露于 最常用的SSRI药物舍曲林和5-HT2B受体(HTR2B)吗啡的应用 心脏发育异常。在美国，有10%的孕妇在 在怀孕期间，这些调查不仅是及时的，而且对于适当地为孕妇提供咨询也至关重要。这个 该提案的总体目标是确定5-羟色胺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 开发和研究特定的基因、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说 通过调节SERT功能。使用变种和变种，她将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， 心脏环，第二心场和房室管的形成。哈斯克尔博士将进一步测试 她的假设是，5-羟色胺系统的破坏通过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，哈斯克尔博士将进行上位性分析，以确定SSRI是否通过SERT起作用 和/或5-HT2B受体影响心脏发育。了解负责以下工作的机制 适应性和非适应性心脏发育将增强我们对心血管生物学的知识 对心脏病儿童的更广泛的影响。

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.