Intervention Strategies for Non-Folate Responsive Neural Tube Defects

摘要 先天缺陷是导致新生儿死亡的主要原因，导致的婴儿死亡人数超过新生儿死亡人数的总和 阿尔茨海默氏症、中风、糖尿病和流感的成人死亡人数。神经管缺陷(NTDS)，第二位 最常见的人类出生缺陷类型，发生在神经管未能正确关闭的时候 神经形成。在全球范围内，这些缺陷估计影响每10,000名活产儿中约18.6人， 在美国大多数地区，NTDS的患病率为每1000名新生儿中有1-2名。大约有2300个新台币- 美国每年受影响的怀孕人数，据估计每个孩子一生的医疗费用为56万美元 或全国每年16.8亿美元。尽管进行了数十年的密集调查，但人们对此知之甚少 潜在的NTD风险因素。人们普遍认为，非关税壁垒是由多种因素引起的，既有 导致畸形的环境和遗传因素。尽管已经确定 围产期使用叶酸(FA)可预防相当大比例的NTDS人群负担， FA降低NTD风险的过程背后的机制尚不清楚。重要的是，在那里 是大量不能通过补充FA预防的NTD，这些抗FA的NTD 以明显的基线比率发生，每10,000名活产儿中有5名。因此，非传染性疾病仍然是一个重要的公共卫生问题。 问题，迫切需要了解FA耐药NTDS的机制，并 针对这一人群制定新的干预策略 为了扩展在最初的筹资阶段所做的工作，我们提出的研究路线探索了机制 线粒体一碳代谢受损是通过什么引起NTDS以及我们建议的干预措施是如何 已成功恢复正确的NTC。同时，我们正在通过以下方式测试疗效和调查机制 哪种甘氨酸补充剂可以挽救这些抗氟烷酸缺陷。建立这些机制并将其与 它们到实际的人类NTD变体可能最终允许我们利用我们提出的干预策略来 通过告知公共卫生政策或精准医学战略来预防以前无法预防的出生缺陷， 从而减轻这些使人衰弱的缺陷对受影响家庭和 公开的。

ABSTRACT Congenital defects are the leading cause of neonatal mortality, resulting in more infant deaths than the combined adult death tolls of Alzheimer’s disease, strokes, diabetes, and influenza. Neural tube defects (NTDs), the second most common category of human birth defects, arise when the neural tube fails to close properly during neurulation. Globally, these defects are estimated to affect approximately 18.6 per 10,000 live births and the prevalence of NTDs is 1–2 per 1,000 births in most regions of the US. There are approximately 2,300 NTD- affected pregnancies in the US each year, whose lifetime medical costs are estimated to be $560,000 per child or $1.68 billion per year nationwide. Despite intensive investigation for decades, relatively little is known about the underlying NTD risk factors. It is generally accepted that NTDs are of a multi-factorial origin, having both environmental and genetic factors that contribute to the malformation. Although it is established that periconceptional use of folic acid (FA) prevents a significant percentage of the population burden of NTDs, the mechanisms underlying those processes by which FA reduces NTD risk remains unknown. Importantly, there are significant numbers of NTDs that are not preventable by FA supplementation, with these FA-resistant NTDs occurring at an apparent baseline rate of 5 per 10,000 live births. Thus, NTDs remain a substantial public health problem, and there is a critical need to understand the mechanisms underlying FA-resistant NTDs and to develop novel intervention strategies targeting this population To expand upon work performed in the initial funding period, our proposed line of study explores mechanisms by which impairment of mitochondrial one carbon metabolism causes NTDs and how our proposed interventions successfully restore proper NTC. Simultaneously, we are testing the efficacy and investigating mechanisms by which glycine supplementation rescues these FA-resistant defects. Establishing these mechanisms and relating them to actual human NTD variants may eventually allow us to utilize our proposed intervention strategies to prevent previously unpreventable birth defects by informing public health policy or precision medicine strategies, thus reducing the significant negative health burden of these debilitating defects on affected families and the public.