Diabetic Pregnancies and Gastrulation

 描述（由申请人提供）：神经形成是形成神经管的发育过程，是神经系统发育中关键而又高度复杂的步骤。这种形态发生过程的缺陷可能导致神经管缺陷，这是人类最致残的出生缺陷之一。神经管缺陷的一个主要原因是怀孕期间的母体糖尿病，其风险高达10倍，导致普遍认为母体糖尿病扰乱了神经管闭合的过程。然而，我们最近的研究结果促使我们对致畸机制提出了一个不同的假设：母体糖尿病通过影响原肠胚形成过程导致出生缺陷。我们认为，致畸性发生在神经胚形成之前，母体糖尿病，通过Nodal，T，Wnt 3a，Fgf 8和Tbx 6等基因的作用，导致异常的原肠胚形成过程，开始于异位中胚层细胞的产生。关于神经管缺陷，我们认为正是这些细胞的存在破坏了神经管闭合的过程。 我们相信这代表了一种范式转变，从燃料介导的致畸作用的一般概念转向分子信号传导过程，不仅控制特定的细胞特性，而且有可能解释为什么神经形成缺陷通常只影响神经管的一小部分。此外，一个原肠胚为基础的致畸机制不仅可以解释神经管缺陷，但也似乎不同的缺陷，心脏，尾区，包括频谱的缺陷称为糖尿病胚胎病。具体来说，我们将结合联合收割机母体和体外葡萄糖调节、培养原条外植体的定量评估和下一代测序技术来确定母体糖尿病和母体血糖如何（i）影响中胚层细胞迁移和清除原条的能力;（iii）改变对原肠胚形成至关重要的基因调控网络的参与;和（iii）在补充叶酸的条件下作用于迁移特性，我们显示叶酸可以改善作为这些研究的模型系统的非肥胖糖尿病小鼠品系的糖尿病妊娠中的神经管缺陷发生率。我们期望该项目的成功完成将为妊娠期母体糖尿病的致畸性带来新的视角，并对该领域产生重大而持续的影响。

 DESCRIPTION (provided by applicant): Neurulation, the developmental process to form the neural tube, represents a critical, yet highly complex step in development of the nervous system. Deficiencies of this morphogenetic process can lead to neural tube defects, one of the most disabling birth defects in humans. One leading cause for neural tube defects is maternal diabetes during pregnancy, with an up to 10-fold higher risk, leading to the prevailing view that maternal diabetes disturbs the process of neural tube closure. However, results from our recent studies prompt us to posit a different hypothesis on the teratogenic mechanism: Maternal diabetes causes birth defects by affecting the process of gastrulation. We suggest that the teratogenicity occurs prior to neurulation, and that maternal diabetes, through the actions of genes such as Nodal, T, Wnt3a, Fgf8, and Tbx6, leads to an aberrant gastrulation process, commencing in the generation of ectopic mesodermal cells. With respect to neural tube defects, we propose that it is the presence of these cells that disrupts the process of neural tube closure. We believe this represents a paradigm shift away from the general concept of fuel-mediated teratogenesis towards a molecular signaling process that not only controls specific cellular properties, but has the potential to explain why neurulation defects usually only affect a small region of the neural tube. Furthermore, a gastrulation-based teratogenic mechanism can explain not only neural tube defects, but also the -seemingly disparate- deficiencies of the heart, and of the caudal region, that comprise the spectrum of defects known as diabetic embryopathy. Specifically, we will combine maternal and in vitro glucose modulation, quantitative assessment of primitive streak explants in culture, and next generation sequencing technology to determine how maternal diabetes and maternal blood glucose can (i) affect the capability of mesodermal cells to migrate and clear the primitive streak; (iii) alter the engagement of gene regulatory networks that are crucial for gastrulation; and (iii) act on migratory properties under conditions f supplementation with folate, which we show can ameliorate neural tube defect incidence in diabetic pregnancies of the Non Obese Diabetic strain of mice that serves as the model system for these studies. We expect that a successful completion of this project will lead to a new perspective on the teratogenicity of maternal diabetes during pregnancy, and to a significant and sustained impact on the field.