环境因素作用于平面细胞极性通路易感基因致人类神经管畸形发生机制的研究

Neural tube defects (NTDs) are the most common and severe malformations of the central nervous system. They result from embryonic failure of neural tube closure that can occur at any level of the embryonic axis. Both genetic and environmental factors are involved in the aetiology of NTDs. The genes variation of the planar cell polarity (PCP) pathway can lead to NTDs. Researchs have published showing the PCP pathway is closely related to NTDs in human cohorts in recent years. As a environmental factors, retinoic acid (RA) can cause NTDs. The genes in PCP pathway may be involved in NTDs caused by RA. However, the mechanism of NTDs by environmental factors on susceptibility gene in PCP pathway remains to be clarified further. Based on the above research background and our previous research findings, in this study we will adopt bioinformatics tools, utilize MassArray biotechnology to detect the PCP susceptibility genes in Han population of Northern China. We will verify the function of susceptibility genes in human NTDs vitro model, and build NTDs animal model by RA to discuss the mechanism of NTDs by environmental factors on susceptibility gene in PCP pathway. Studies of this project are expected to provide some evidence on early diagnosis and drug screening by interposed PCP pathway.

神经管畸形(NTDs)是胚胎发育早期神经管闭合障碍引起的中枢神经系统畸形，与环境和遗传因素交互作用相关。研究表明平面细胞极性(PCP)通路核心基因突变可致NTDs。近年来不同人群研究也发现该通路基因与人类NTDs发生密切相关。维甲酸(RA)作为一种环境因素过量可致NTDs发生。研究报道PCP通路基因可能参与RA导致的NTDs发生。但环境因素作用于PCP通路易感基因致人类NTDs发生机制有待进一步阐明。基于以上研究背景、项目组既往研究结果及所收集样本信息，本研究拟利用生物信息学工具及MassArray分子量阵列等技术，明确PCP通路中存在的中国北方汉族人群NTDs相关易感基因并在人类神经管体外模型中验证易感基因功能；通过建立维甲酸 NTDs动物模型，以探讨环境因素作用于PCP通路致NTDs发生的具体机制，为NTDs的早期诊断以及筛选通过干预PCP信号通路防治NTDs的药物靶标提供科学依据。

神经管畸形(NTDs)是胚胎发育早期神经管闭合障碍引起的中枢神经系统畸形。NTDs是环境因素、遗传因素、表观遗传学等多因素作用的疾病。研究表明平面细胞极性(PCP)通路、叶酸代谢通路中核心基因的突变可引发NTDs，基因组DNA甲基化也与NTDs发生相关。作为环境因素，维甲酸（RA）过量可引起NTDs的发生，而补充叶酸可以有效降低NTDs发生率。本研究利用生物信息学工具及MassArray分子量阵列技术等，明确PCP信号通路、叶酸代谢通路中存在的中国北方汉族人群NTDs相关的易感基因，通过建立维甲酸 NTDs动物模型，以探讨环境因素作用于PCP信号通路导致NTDs的发生机制。研究结果发现：在中国北方汉族人群儿童中发现了叶酸代谢通路中7个基因的12个SNPs位点可增加NTDs发生风险，包括BHMT基因rs3733890、MTHFD1基因rs2236224/rs2236225、MTHFR基因rs1801133、MTR基因rs1805087、MTRR基因rs10380/rs162036/rs1801394/rs9332、RFC1基因rs1051266/rs3788200以及TYMS基因rs502396；基因型交互作用分析，得出SNP-SNP之间存在较为显著的交互作用。在中国北方汉族NTDs家系中，NTDs患者基因组DNA甲基化异常，DNA甲基化异常可能是增加NTDs发病的危险因素。该研究为NTDs的早期诊断以及筛查提供科学依据。