Diabetic Pregnancies and Gastrulation

 描述(申请人提供)：神经形成，形成神经管的发育过程，代表了神经系统发育中的一个关键但高度复杂的步骤。这种形态发生过程的缺陷可能会导致神经管缺陷，这是人类最具致残性的出生缺陷之一。神经管缺陷的一个主要原因是妊娠期的母亲糖尿病，风险高达10倍，导致普遍认为母亲的糖尿病扰乱了神经管关闭的过程。然而，我们最近的研究结果促使我们对致畸机制提出了不同的假设：母体糖尿病通过影响原肠形成过程导致出生缺陷。我们认为，畸形发生在神经发生之前，母体糖尿病通过Nodal、T、Wnt3a、Fgf8和Tbx6等基因的作用，导致异常的原肠形成过程，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扰乱了神经管关闭的过程。 我们认为，这代表着一种范式的转变，从燃料介导的畸形发生的一般概念转向分子信号过程，该过程不仅控制特定的细胞属性，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，基于原肠作用的致畸机制不仅可以解释神经管缺陷，还可以解释心脏和尾部区域的-似乎完全不同的-缺陷，这些缺陷构成了被称为糖尿病胚胎病变的缺陷谱。具体地说，我们将结合母体和体外葡萄糖调节、对培养中原始条纹外植体的定量评估，以及下一代测序技术来确定母体糖尿病和母体血糖如何能够(I)影响中胚层细胞迁移和清除原始条纹的能力；(Iii)改变对原肠形成至关重要的基因调控网络的参与；以及(Iii)在补充叶酸的条件下对迁移特性起作用，我们证明叶酸可以改善糖尿病妊娠小鼠的神经管缺陷发生率，这是这些研究的模型系统。我们预计，该项目的成功完成将导致对孕期糖尿病致畸性的新看法，并对这一领域产生重大和持久的影响。

 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.