Impact of different causes of intrauterine growth restriction in the rat on early neurodevelopment and long-term neurocognitive outcome

• Applicant: Dr. Kai-Dietrich Nüsken
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233156887

Intrauterine growth restriction (IUGR) can be caused by numerous different conditions, which are often not accounted for in the clinical setting. Experimentally, we have previously shown that fetal programming of metabolic and cardiovascular morbidity in later life depends on the cause of IUGR by comparing two clearly different, pathophysiologically well defined models of IUGR in the rat (low protein nutrition vs. bilateral uterine artery ligation). However, an increased susceptibility is known not only for metabolic and cardiovascular sequelae, but also for neurocognitive and anxiety disorders. Therefore, the goal of the present proposal is to clearly assign mechanistic links between placental abnormalities, disturbed early neurodevelopment and medium- to long-term behavioral abnormalities by differentiating the impact of above mentioned models on placental, neuronal and behavioral parameters. In detail, we will study morphologic and molecular changes in term placentae and in the developing brain of IUGR rats aged 1 to 12 days (collaborations with Prof. Dr. Felderhoff-Müser and Dr. Gellhaus, Essen). On the molecular level, we will focus on placental and hippocampal gene expression and gene methylation by performing a whole genome microarray and analyzing the DNA methylation pattern in neonatal rats (collaboration with Dr. Plösch, Groningen, NL). Relevant genes will be further analyzed by quantitative RT-PCR and protein quantification at all time points. At the age of 1, 3 and 6 months, rats will be subjected to behavioral testing. In conclusion, our goal is to differentiate which pathophysiological cause of IUGR particularly predisposes for neurocognitive disorders. Additionally, we aim to elucidate mechanisms of brain damage to evolve potential preventive strategies.

• DFG Programme: Research Grants
• Participating Person: Dr. Eva Nüsken