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Influence of maternal metabolic state on placental and neonatal serotonin system: from DNA methylation to protein function

Principal investigator

Category
Projekti Hrvatske zaklade za znanost
Project code
IP-2018-01-6547
Finance value
990.000,00
HRK
Start date
Dec 1st 2018
End date
Nov 30th 2022
Status
Done

Serotonin (5HT) is a multifunctional signaling molecule, best known as the central nervous system neurotransmitter. In addition, 5HT plays important extra-cerebral roles, both in adulthood and during development. Disturbed 5HT homeostasis has been linked to many mental health conditions and is emerging as important contributor also to obesity and related metabolic disorders. However, causes of 5HT disturbances are yet poorly understood. Rising evidence suggests that DNA methylation, a dynamic process sensitive to environmental cues, plays a crucial role in the regulation of 5HT signaling through modifying transcriptional activity of genes encoding 5HT-regulating proteins (transporters, receptors and enzymes). In order to search for early developmental origins of altered 5HT functioning in humans, here we aim to establish a comprehensive biobank of human perinatal specimens and investigate the impact of altered maternal metabolic state in pregnancy on placental and the newborn's 5HT system. We hypothesize that maternal metabolic, proinflammatory and/or endocrine changes associated with obesity and gestational diabetes mellitus (GDM) may affect placental and fetal 5HT system through DNA methylation-mediated mechanisms. Hence, we aim to: 1) explore the relationship of maternal gestational glycemia and pregestational body mass index (pBMI) with placental DNA methylation and expression of 5HT-related genes known to be functional in human placental cells; 2) explore the relationship of maternal gestational glycemia and pBMI with the newborn's 5HT system by quantifying cord blood DNA methylation of multiple 5HT-regulating genes and measuring cord blood 5HT-related biochemical/functional parameters (5HT level, platelet 5HT uptake and platelet aggregation); 3) investigate in vitro effects of glucose and inflammatory cytokines on DNA methylation and expression of 5HT-related genes as well as on function of the corresponding gene products in human placental cells (trophoblasts and fetoplacental endothelial cells). The obtained results will increase our knowledge about molecular mechanisms that regulate 5HT system during early human development and may lead to better understanding of conditions associated with disturbed 5HT homeostasis.

Research Team

  • Maja Perić, Ruđer Bošković Institute
  • Marina Horvatiček, Ruđer Bošković Institute
  • Ivona Bečeheli, Ruđer Bošković Institute
  • Lipa Čičin-Šain, Ruđer Bošković Institute
  • Maja Kesić, Ruđer Bošković Institute
  • Marina Ivanišević, Clinical Hospital Centre Zagreb
  • Mirta Starčević, Clinical Hospital Centre Zagreb
  • Saša Kralik, Clinical Hospital Centre Zagreb
  • Maja Žutić, Catolic University of Croatia, Department of Psychology
  • Sandra Nakić Radoš, Catolic University of Croatia, Department of Psychology
  • Maja Anđelinović, Catolic University of Croatia, Department of Psychology
  • Dubravka Hranilović, University of Zagreb, Faculty of Science
  • Barbara Nikolić, University of Zagreb, Faculty of Science
  • Gernot Desoye, Medical University of Graz

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