血浆铜蓝蛋白作为神经管畸形胚胎早期诊断分子标志物的价值及其机制探讨

课题组利用蛋白质组学技术发现16种蛋白质在神经管畸形孕妇血清中存在差异表达，经过进一步验证确定血浆铜蓝蛋白（CP）在神经管畸形诊断中有较好的敏感性和特异性，优于目前在临床上应用的AFP检测。因此，本课题将进行多中心、大样本的临床验证，并与其它先天畸形进行比较，同时探讨CP能否作为结构异常发现之前的早期筛查指标，为这一新的分子标志物能够在临床广泛应用提供依据。同时结合课题组前期研究结果，提出CP参与神经管畸形发生的新假设，即由于CP蛋白质折叠错误引发内质网应激反应，同时由于CP功能异常引起金属离子代谢异常和氧化应激损伤又进一步加重神经细胞破坏，最后导致畸形发生。本课题将建立动物模型，从不同胚胎发育阶段观察CP在神经管组织的表达规律、蛋白质折叠、铜离子代谢和氧化应激损伤等指标变化，探讨CP导致神经管畸形的可能机制，同时提出以CP和内质网应激反应通路中的关键基因为靶点的神经管畸形治疗新方法。

Neural tube defects (NTDs) is the most serious congenital malformation harmful to human health and its embryogenesis is still not clear. Using proteomics technology we have found 16 upregulated proteins in serum pregnant women with neural tube defects. After further verification, ceruloplasmin (CP) has good sensitivity and specificity in the diagnosis of neural tube defects and it is better than AFP. All of those indicate CP is likely to be a very valuable molecular markers in noninvasive diagnosis of NTDs.Therefore, we will take advantages of the cooperation with a number of domestic birth defects research centers for multicenter and large sample validation, and compare with other common congenital malformations. At the same time, we will study whether the CP could be a biomarker for early screening. Our study may provide scientific basis for this new molecular markers widely used in clinical. In combination with our previous studies, we for the first time suppose that CP is involved in the occurrence of NTDs, that is due to some genetic or environmental abnormal factors, CP protein misfold, which trigger endoplasmic reticulum stress reaction, and lead to the excessive apoptosis of neuroepithelial cells. At the same time, metal ion metabolic abnormalities and oxidative stress damage caused by CP dysfunction further aggravate nerve cell damage and lead ultimately to the occurrence of NTDs. In order to verify the new hypothesis, in this study we will establish the animal model of NTDs to observe the CP expression, protein folding, copper ion metabolism and oxidative stress injury in neural tube from different embryonic developmental stage. We will explore the exact mechanism of CP in embryogenesis of NTDs, and put forward new treatments targeting key genes of endoplasmic reticulum stress reaction pathways for NTDs. This study belongs to the innovative research,and there is no similar study has been reported until now. It is great significant to reduce the occurrence and improve the quality of life in children with birth defects.