Neural tube defects in diabetic pregnancy

糖尿病妊娠的神经管缺陷

基本信息

批准号：
7781361
负责人：
J Michael Salbaum
金额：
$ 43.1万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-15 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7781361
关键词：
Adult Affect Birth Cardiovascular Diseases Cardiovascular system Child Chronic Disease Congenital Abnormality Data Defect Development Diabetes Mellitus Disease Embryo Embryonic Development Environment Exposure to Failure Frequencies Future Gene Expression Gene Targeting Genes Genetic Genetic Models Genetic Predisposition to Disease Goals Health Hypertension Hypoxia Incidence Individual Infant Knowledge Life Longevity Maps Measures Mediating Mesoderm Metabolic syndrome Metabolism Modeling Molecular Molecular Profiling Morbidity - disease rate Morphogenesis Mus Mutant Strains Mice Nervous system structure Neural Tube Closure Neural Tube Defects Neural Tube Development Neural tube Neuraxis Nutritional Outcome Study Oxidative Stress Pathogenesis Platelet-Derived Growth Factor Play Predisposition Pregnancy Pregnancy in Diabetics Prevalence Public Health Research Personnel Risk Role Signal Pathway Signal Transduction Staging Subgroup System Teratogens Testing United States Vinculin Woman Work adverse outcome base diabetic diabetic embryopathy experience gene interaction in utero malformation maternal diabetes member mortality mutant nervous system development next generation novel prenatal exposure prevent programs research study response transcription factor type I and type II diabetes

项目摘要

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.

描述（由申请人提供）：糖尿病是美国和全世界的一个主要健康问题。 I型和II型糖尿病不仅严重损害患者的健康，而且糖尿病还会影响胚胎发育。怀孕期间的母亲糖尿病具有明确的致畸作用，可导致出生缺陷，例如心血管畸形和神经管缺陷。这些影响尚不清楚，但被认为涉及胚胎基因构成与子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，重点关注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，糖尿病妊娠期间母体代谢异常会导致胚胎早期神经系统发育过程中的基因表达失调，从而导致神经管缺陷的发生率增加。这一假设的基础是我们最近发现了 143 个基因，这些基因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。已知其中许多基因与出生缺陷有关，其中一部分基因在神经管缺陷中发挥作用。我们现在建议（1）定义哪些基因最具指示性，并且可以作为神经管无法正常关闭的预测标记； (2) 研究改变的缺氧反应，特别是在暴露于糖尿病的胚胎中发现的Hifla表达减少，如何损害胚胎成功适应不利的宫内环境的能力； (3) 确定糖尿病调控基因 PdgfRa 和 Vinculin 如何介导因宫内暴露于母亲糖尿病而导致的神经管缺陷的易感性。随着美国年轻女性糖尿病患病率的不断上升，下一代的产前暴露成为一个主要的健康问题。子宫内接触糖尿病是导致严重出生缺陷和慢性疾病（例如代谢综合征、高血压和心血管疾病）的已知风险。了解发育中胚胎中对母亲糖尿病有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。