Diabetic Pregnancies and Gastrulation

糖尿病妊娠和原肠胚形成

• 批准号: 9295057
• 负责人: J Michael Salbaum
• 金额: $ 30.71万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-07 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295057
• 关键词: Acute; Affect; Antioxidants; Biological Assay; Biological Models; Biological Process; Blood Glucose; Cell physiology; Cells; Chemicals; Chronic; Complex; Congenital Abnormality; Data; Defect; Development; Developmental Process; Diabetes Mellitus; Embryo; Embryonic Development; Etiology; Exposure to; FGF8 gene; Folic Acid; Gene Expression; Generations; Genes; Glucose; Growth; Heart; Heart Abnormalities; Histologic; Human; Impairment; In Vitro; Incidence; Insulin-Dependent Diabetes Mellitus; Kinetics; Laboratories; Lead; Maintenance; Measures; Mediating; Mesoderm; Mesoderm Cell; Modeling; Molecular; Mouse Strains; Mus; Neural Tube Closure; Neural Tube Defects; Neural tube; Nodal; Non obese; Outcomes Research; Pathway interactions; Phenotype; Pregnancy; Pregnancy in Diabetics; Primitive Streaks; Process; Property; Regulator Genes; Research Project Grants; Role; Signal Transduction; Technology; Teratogens; Testing; Tissues; WNT3 gene; base; cell motility; design; diabetic; diabetic embryopathy; experimental study; folic acid supplementation; gastrulation; high risk; in vivo; interest; malformation; maternal diabetes; maternal hyperglycemia; migration; mouse model; nervous system development; neural plate; next generation sequencing; non-diabetic; novel; prevent; public health relevance; response; theories

 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.

 描述（由申请人提供）：神经形成，即形成神经管的发育过程，代表了神经系统发育中关键但高度复杂的步骤，该形态发生过程的缺陷可能导致神经管缺陷，这是最严重的残疾之一。人类出生缺陷的一个主要原因是母亲在怀孕期间患有糖尿病，其风险高达 10 倍，因此普遍认为母亲糖尿病会扰乱神经管闭合过程。我们最近的研究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，而母亲糖尿病是通过Nodal等基因的作用而发生的。 、T、Wnt3a、Fgf8 和 Tbx6 导致异常原肠胚形成过程，开始产生异位中胚层细胞，我们建议。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转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的看似不同的缺陷，其中包括称为糖尿病胚胎病的一系列缺陷。我们将结合母体和体外葡萄糖调节、培养物中原纹外植体的定量评估以及下一代测序技术，以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；以及 (iii) 在补充叶酸的条件下作用于迁移特性，我们证明这可以改善非肥胖糖尿病妊娠患者的神经管缺陷发生率作为这些研究模型系统的糖尿病小鼠品系，我们期望该项目的成功完成将为妊娠期间母亲糖尿病的致畸性带来新的视角，并对该领域产生重大和持续的影响。