Diabetic Pregnancies and Gastrulation

 描述（由申请人提供）：神经形成，即形成神经管的发育过程，代表神经系统发育中关键但高度复杂的步骤。这种形态发生过程的缺陷可能导致神经管缺陷，这是人类最严重的出生缺陷之一。神经管缺陷的主要原因之一是孕期母亲患有糖尿病，其风险高出 10 倍，因此人们普遍认为母亲糖尿病会干扰神经管闭合过程。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：母亲糖尿病通过影响原肠胚形成过程而导致出生缺陷。我们认为致畸性发生在神经形成之前，并且母体糖尿病通过 Nodal、T、Wnt3a、Fgf8 和 Tbx6 等基因的作用，导致异常的原肠胚形成过程，开始产生异位中胚层细胞。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。 我们认为，这代表了从燃料介导的致畸一般概念向分子信号传导过程的范式转变，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区域。此外，基于原肠胚形成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看似不同的缺陷，这些缺陷包括被称为糖尿病胚胎病的一系列缺陷。具体来说，我们将结合母体和体外葡萄糖调节、培养中原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（i）影响中胚层细胞迁移和清除原纹的能力； (iii) 改变对原肠胚形成至关重要的基因调控网络的参与； (iii)在补充叶酸的条件下作用于迁移特性，我们证明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神经管缺陷的发生率。我们期望该项目的成功完成将为孕产期糖尿病致畸性提供新的视角，并对该领域产生重大和持续的影响。

 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.