尿道发育动力学及维生素E预防尿道下裂发生机制研究

Hypospadias is one of the most common congenital genitourinary malformation of children, its incidence is increasing year by year. In our previous work, we found that DEHP (a sort of plasticiser) which acts as an environmental endocrine disruptor can induce animal hypospadias, and vitamin E can effectively resist the toxicity. However, the mechanism is not clear. Based on our previous research work, we planning to investigate the mechanism of urethral formation and its genetic regulation. Focusing on the epithelium of fetal urethral plate in key developmental period, the research work of this project includs developmental dynamics of urethra (cellular apoptosis,migration and epithelial mesenchymal transformation) and the genetic and protein expressions. By using comparative genomics and proteomic, epigenetics and toxicology et al methods, the cellular morphology, function of urethral plate of hypospadic animal model and the relationship with particular genes and proteins will be explored. The ultimate aim is verifying the mechanism of preventive and side effects of vitamin E on hypospadic rat. We are certain that this work will provide experimental evidence for clinical prevetion of genitourinary malformation.

尿道下裂是小儿最常见的泌尿生殖道先天畸形之一，发病率逐年上升。课题组前期研究发现环境内分泌干扰物DEHP（一种增塑剂）可导致动物尿道下裂，而维生素E能够有效拮抗尿道下裂发生，其机制尚不清楚。本项目拟在前期系列研究基础上，针对处于发育关键期的胎鼠尿道板上皮细胞，从尿道发育动力学角度（细胞凋亡、细胞迁移、上皮-间质转化）以及基因、蛋白表达等多方面，深入探讨尿道发育形成过程及其基因调控机制；进一步采用比较基因组与蛋白组学、表观遗传学、毒理学等方法探索尿道下裂动物模型其尿道板上皮细胞形态、功能等异常与相关基因、蛋白的关系，揭示尿道下裂发生机制；最终旨在探究维生素E预防尿道下裂发生机制，完善其安全性评估。本研究必将为临床预防生殖畸形的发生提供科学的实验依据。

尿道下裂是小儿常见的先天性泌尿生殖畸形，发病率高，危害性大，但尿道下裂的发病机制尚不清楚。本研究主要通过大鼠为实验模型，探索正常尿道的发育动力学及尿道板的融合机制，为尿道下裂发生机制研究提供基础，为临床防治尿道下裂提供科学依据。本研究通过电镜、免疫双标、蛋白印迹、RNA-seq、器官培养等实验方法，发现尿道是通过尿道板由近端向远端逐渐卷曲融合而成。在尿道板融合过程中，我们在国内外首次发现尿道板上皮细胞存在上皮-间质转化现象，从全新角度阐释了尿道形成机制。.在此基础上，课题组发现环境污染物DEHP可通过抑制尿道板上皮-间质转化，促进细胞凋亡，进而阻碍尿道缝融合导致尿道下裂发生。为进一步揭示DEHP致畸分子生物学机制，课题组通过RNA-seq技术筛选并初步验证RBP家族可从多种信号通路或效应分子影响尿道的发育，提示对RBP家族的研究在尿道下裂发生机制及预防等领域具有广阔前景，相关研究仍在深入中。另一方面，课题组从预防角度出发，发现维生素E及TGF-β1能有效的拮抗DEHP所致的尿道发育毒性，纠正机体氧化应激失衡，激活Nrf2-HO1信号通路，进而保护尿道板正常的上皮-间质转化及凋亡过程，减少尿道下裂的发生。