HtrA4经内质网应激调控滋养细胞自噬在子痫前期发生中作用及机制研究

Trophoblast cells dysfunction has played a key role in the occurrence of preeclampsia. Endoplasmic reticulum stress is a regulatory mechanism of misfolded proteins, which helps to restore the cell function. Our preliminary data suggested that the endoplasmic reticulum stress level in PE trophoblast increased significantly, and the expression of a misfolded protein regulator HtrA4 also increased. This evidence suggests the HtrA4 as a regulator of endoplasmic reticulum stress, but its activity may has decreased. Besides, we have confirmed the level of autophagy in preeclampsia has increased. Endoplasmic reticulum stress could be a promotor of autophagy, which has been reported in other cell lines. Furthermore, the p-JNK expression in the PE trophoblast cells has increased according to our preliminary study. Activation of JNK signal is a result of endoplasmic reticulum stress, however, it is also a promoter signal of autophagy. Based on the above data, we will further discuss the role of HtrA4 in ERS-autophagy regulation, and analysis its possible molecular mechanisms. We propose by adjusting HtrA4 can we provide a new target for PE treatment and finally improve the prognosis of preeclampsia.

滋养细胞功能异常是子痫前期发生的重要病理生理基础。内质网应激作为一种对折叠错误蛋白进行调控的机制，其发生有助于解除细胞内的异常状态。本项目组前期实验发现，子痫前期胎盘中内质网应激水平显著升高，而一种可对折叠错误蛋白进行质控的HtrA4的表达也显著上升。这提示HtrA4参与内质网应激调控，但其活性可能出现异常降低。此外，我们还发现子痫前期胎盘中自噬水平显著上升。有报道显示在某些细胞中内质网应激可导致自噬发生，并参其调控。JNK信号的活化不仅是内质网应激的结局，也是自噬的启动信号。项目组通过检测子痫前期胎盘组织p-JNK证实其表达升高。因此，我们推测滋养细胞JNK信号在内质网应激-自噬过程中发挥了重要作用。本研究拟以前期工作为基础，以子痫前期滋养细胞为研究对象，以内质网应激为切入点，深入探讨HtrA4对内质网应激-自噬的调控作用，以期阐明其分子机制，并最终为子痫前期的防治提供一种新的思路。

滋养细胞功能异常是子痫前期发生的重要病理生理基础。内质网应激作为一种对错误折叠蛋白进行调控的机制，其发生有助于解除细胞内的异常状态，一定程度上是一种积极的生理过程。本项目经实验发现，子痫前期患者，特别是早发型子痫前期患者中，胎盘中一种对错误折叠蛋白进行质控的蛋白HtrA4表达显著上升，且其表达量与子痫前期病情严重程度相关。与此对应的，HtrA蛋白家族的整体活性升高、内质网应激水平升高。而且，HtrA4的蛋白表达与内质网应激水平相关。此外，我们在BeWo细胞系中，验证了HtrA4及ERS之间的相互作用，并且发现两者的调控关系影响到滋养细胞合胞化过程。同时，以原代滋养细胞为基础的体外实验也证实了猜想，即一定程度的ERS将促进合胞化的进行，而HtrA4的过量表达则阻碍了这样一个过程，从而可能参与到子痫前期的发生发展。本研究从分子水平上阐明了HtrA4及ERS参与子痫前期发生发展的可能机制，为后续子痫前期等胎盘缺血性疾病的机制研究提供基础。