Role of Slc25a32 and Its Interaction with Lrp6 in the Etiology of Neural Tube Defects

摘要 神经管缺陷(NTD)是人类第二种最常见的结构性出生缺陷，导致 在神经形成过程中神经管关闭(NTC)失败。已知NTDS的病因是多方面的。 因素，包括相互作用的遗传和环境因素。有多个与发育相关的 NTC参与的信号通路在空间和时间上都有进展。特定基因的鉴定 对NTDS的病因学有重大贡献的变异体及其潜在分子的特征 在过去的几十年里，导致NTC失败的细胞机制进展缓慢。是什么 需要认识到的重要一点是，NTDS是一种可以预防的出生缺陷。跨越数十年的研究 证实孕妇孕周补充叶酸可以将NTDS的风险降低30% 降至70%。然而，并不是所有的NTD都对叶酸有反应。目前，30%-50%的非传染性疾病无法通过以下方式预防 补充叶酸。建议的研究项目是基于我们最近发表的叶酸非 反应性SLC25a32缺失小鼠模型及其与叶酸反应性Wnt共受体LRP6的相互作用 突变小鼠模型。这些研究旨在帮助阐明心力衰竭的潜在机制 并验证我们的假设，即这些叶酸抵抗的NTD可以通过以下方法预防 干预下游叶酸代谢物，如甲酸盐。最近确定甲酸盐可以 挽救叶酸抗性的NTD小鼠，提示线粒体一碳代谢可能是 在对非叶酸反应的NTD人群中受到损害。尽管经过了近40年的密集研究，我们仍然 不完全了解叶酸依赖的分子、细胞和生化机制 全国过渡委员会的进程。我们知识上的这种差距阻碍了我们做出明智的卫生政策决策的能力 叶酸强化，并确定新的治疗方法，以防止叶酸抵抗性NTDS。

ABSTRACT Neural tube defects (NTDs) are the second most common type of structural birth defects in humans, resulting from the failure of neural tube closure (NTC) during neurulation. The etiology of NTDs are known to be multi- factorial, including interacting genetic and environmental factors. There are multiple developmentally-related signaling pathways involved as NTC proceeds spatially and temporally. The identification of specific genetic variants that contribute significantly to the etiology of NTDs, and the characterization of their underlying molecular and cellular mechanisms leading to failed NTC has progressed slowly over the last several decades. What is important to recognize is that NTDs stand out as a preventable birth defect. Research spanning decades demonstrates that maternal periconceptional supplementation with folic acid can reduce the risk of NTDs by 30% to 70%. Yet not all NTDs are folate responsive. Currently between 30-50% of all NTDs are not preventable by folic acid supplementation. The proposed research project is based on our recently published folic acid non- responsive Slc25a32 null mouse model, and its interaction with a folic acid responsive Wnt co-receptor, Lrp6 mutant mouse model. The studies are designed to help elucidate the underlying mechanisms characteristic of folic acid resistant NTDs, and to test our hypothesis that these folate resistant NTDs may be prevented by interventions with downstream folate metabolites, such as formate. It was recently determined that formate could rescue folic acid-resistant NTD mice, suggesting that mitochondrial one carbon metabolism might be compromised in the non-folate responsive NTD population. Despite almost 40 years of intensive study, we still do not fully understand the molecular, cellular and biochemical mechanisms that underlie the folate-dependent process of NTC. This gap in our knowledge hinders our ability to make informed health policy decisions about folate fortification and to identify novel treatments to prevent folate-resistant NTDs.