Neural tube defects in diabetic pregnancy

描述（由申请人提供）：糖尿病是美国和世界范围内的主要健康问题。1型和2型糖尿病不仅严重损害患者的健康，而且还会影响胚胎发育。怀孕期间的孕妇糖尿病有充分的证据证明会导致出生缺陷，如心血管畸形和神经管缺陷。这些影响尚不清楚，但被认为与胚胎的基因组成与宫内环境的相互作用有关。该项目的目标是了解母体糖尿病如何影响发育中的胚胎，重点关注早期神经系统和神经管缺陷的发病机制。我们的主要假设是，糖尿病妊娠期间母体代谢异常导致胚胎早期神经系统发育过程中基因表达失调控，从而导致神经管缺陷发生率增加。这一假设的基础是我们最近发现的143个基因，它们的表达在发育过程中暴露于母体糖尿病的小鼠胚胎中发生了显著变化。已知这些基因中的许多与出生缺陷有关，其中一部分基因在神经管缺陷中起作用。我们现在建议(1)确定哪些基因是最有指示性的，可以作为神经管关闭失败的预测标记；(2)研究缺氧反应的改变，特别是在糖尿病暴露的胚胎中发现的Hifla表达的降低，是如何损害胚胎成功适应不良宫内环境的能力的；(3)确定糖尿病调控基因PdgfRa和Vinculin如何介导宫内暴露于母体糖尿病导致神经管缺陷的易感性。随着美国年轻女性糖尿病患病率的增加，下一代产前暴露成为一个主要的健康问题。众所周知，在子宫内接触糖尿病会导致严重出生缺陷和慢性疾病，如代谢综合征、高血压和心血管疾病。了解发育中胚胎对母体糖尿病反应的特定遗传因素将为未来预防糖尿病妊娠不良后果的策略奠定基础。

DESCRIPTION (provided by applicant): Diabetes is a major health concern in the United States and worldwide. Both type I and type II diabetes not only severely compromise the health of the afflicted individual, but diabetes also affects embryonic development. Maternal diabetes during pregnancy has well-documented teratogenic effects that cause birth defects such as cardiovascular malformations and neural tube defects. Those effects are not well understood, but are thought to involve interactions of the embryo's genetic makeup with the intrauterine environment. The goal of this project is to understand how maternal diabetes affects the developing embryo, with focus on the early nervous system and the pathogenesis of neural tube defects. Our key hypothesis is that abnormal maternal metabolism in diabetic pregnancy de-regulates gene expression during early nervous system development in the embryo, thereby leading to an increased incidence of neural tube defects. The basis for this hypothesis is our recent discovery of 143 genes whose expression is significantly changed in mouse embryos exposed to maternal diabetes during development. Many of these genes are already known to be involved in birth defects, and a subset of these genes play a role in neural tube defects. We now propose (1) to define which genes are most indicative and can serve as predictive markers for failure of the neural tube to close properly; (2) to investigate how an altered hypoxia response, in particular reduced Hifla expression as found in diabetes-exposed embryos, compromises the embryo's ability to successfully adapt to the adverse intrauterine environment; (3) to determine how the diabetes regulated genes PdgfRa and Vinculin mediate the susceptibility to neural tube defects as consequence of the intrauterine exposure to maternal diabetes. With increasing prevalence of diabetes in younger women in the United States, prenatal exposure of the next generation becomes a major health concern. Exposure to diabetes in utero is a known risk for severe birth defects and for chronic disease, such as metabolic syndrome, hypertension and cardiovascular disease. Understanding the specific genetic factors in the developing embryo that respond to maternal diabetes will form the basis for future strategies to prevent the adverse outcomes of diabetic pregnancies.