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

宫内生长受限（IUGR）可以由许多不同的条件引起，这些条件通常在临床环境中无法解释。在实验上，我们以前已经表明，胎儿规划的代谢和心血管疾病的发病率在以后的生活取决于IUGR的原因，通过比较两个明显不同的，病理生理学定义明确的模型IUGR的大鼠（低蛋白质营养与双侧子宫动脉结扎）。然而，增加的易感性不仅是已知的代谢和心血管后遗症，而且对神经认知和焦虑障碍。因此，本提案的目标是通过区分上述模型对胎盘、神经元和行为参数的影响，明确胎盘异常、早期神经发育紊乱和中长期行为异常之间的机制联系。详细地说，我们将研究足月胎盘和1至12日龄IUGR大鼠发育中大脑的形态学和分子变化（与Felderhoff-Müser教授和Gellhaus博士合作，埃森）。在分子水平上，我们将通过进行全基因组微阵列和分析新生大鼠的DNA甲基化模式（与Plösch博士合作，荷兰格罗宁根），专注于胎盘和海马基因表达和基因甲基化。在所有时间点通过定量RT-PCR和蛋白定量进一步分析相关基因。在1、3和6月龄时，对大鼠进行行为测试。总之，我们的目标是区分IUGR的病理生理原因，特别是易患神经认知障碍。此外，我们的目标是阐明脑损伤的机制，以发展潜在的预防策略。

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.