Impact of disruptions in the serotonin system on cardiac development

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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.