转录因子Pax5调控肌动蛋白结合蛋白诱导线粒体凋亡在神经管畸形发生过程中的作用机制研究

神经管畸形（NTDs）是一类严重的致死性中枢神经系统先天畸形，其发生机制尚不明确。申请者前期发现NTDs胎鼠存在氧化损伤以及线粒体功能障碍。通过iTRAQ技术筛选并验证了肌动蛋白结合蛋白Coro1a、Tagln2和Tpm4在NTDs组低表达。通过软件预测发现Coro1a、Tagln2和Tpm4可能受转录因子Pax5的转录调控，此外三者可能抑制Arp2/3复合体介导的F-actin核化。我们提出假说：由于转录因子Pax5对Coro1a、Tagln2和Tpm4异常调控，降低了对Arp2/3复合体的抑制，促进F-actin核化，导致ROS增加，线粒体损伤，神经细胞凋亡，NTDs发生。本课题将明确Pax5的转录调控作用，分析Coro1a，Tagln2和Tpm4与Arp2/3复合体的作用关系，阐明F-actin核化与线粒体凋亡在NTDs形成中的作用，为NTDs发生提供理论依据以及临床治疗干预靶点。

Neural tube defects (NTDs) are a serious and fatal congenital malformation of the central nervous system. The pathogenesis of NTDs is still unclear. The applicant previously found that NTDs fetal mice had oxidative damage and mitochondrial dysfunction. iTRAQ technology was used to screen and verify the low expression of actin binding proteins Coro1a, Tagln2 and Tpm4 in NTDs group. The software predicted that Coro1a, Tagln2 and Tpm4 may be regulated by transcription factor Pax5. In addition, Coro1a, Tagln2 and Tpm4 may inhibit Arp2/3 complex mediated F-actin nucleation. We hypothesized that the abnormal regulation of transcription factor Pax5 on Coro1a, Tagln2 and Tpm4 can reduce the inhibition of Arp2/3 complex, promote F-actin nucleation, increase ROS accumulation, cause mitochondrial damage, induce neuronal apoptosis, and eventually cause NTDs. This project will clarify the transcriptional regulation of Pax5 on Coro1a, Tagln2 and Tpm4, analyze the relationship between Coro1a, Tagln2 and Tpm4 and Arp2/3 complex, clarify the role of F-actin nuclearization and mitochondrial apoptosis in the formation of NTDs, which will provide an important research basis for revealing the mechanism of NTDs development, and finally find new targets for clinical treatment.