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一个主要的健康问题。I型和II型糖尿病不仅严重危害患者的健康，而且还会影响胚胎发育。孕妇怀孕期间的糖尿病具有众所周知的致畸作用，会导致出生缺陷，如心血管畸形和神经管缺陷。这些影响还不是很清楚，但被认为涉及胚胎的基因构成与宫内环境的相互作用。该项目的目标是了解母亲糖尿病如何影响发育中的胚胎，重点是早期神经系统和神经管缺陷的发病机制。我们的关键假设是，糖尿病妊娠时母体代谢异常会破坏胚胎神经系统发育早期的基因表达，从而导致神经管缺陷的发生率增加。这一假说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着变化。已知这些基因中的许多与出生缺陷有关，这些基因的一个子集在神经管缺陷中发挥作用。我们现在提议(1)定义哪些基因最具指示性，并可作为神经管无法正常关闭的预测标记物；(2)研究缺氧反应的变化，尤其是在糖尿病暴露的胚胎中发现的Hifla表达降低如何损害胚胎成功适应不利宫内环境的能力；(3)确定糖尿病调节基因PDGFRA和vinculin如何介导因母亲糖尿病宫内暴露而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。在子宫中接触糖尿病是严重出生缺陷和慢性疾病的已知风险，如代谢综合征、高血压和心血管疾病。了解发育中胚胎中对母亲糖尿病作出反应的特定遗传因素将成为未来预防糖尿病妊娠不良后果的战略的基础。

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.