FAM134B介导的内质网过度自噬导致钙离子异常释放在PE发病中的作用机制研究

绒毛外滋养细胞（EVT）侵袭力受损所致的胎盘血管重铸障碍是子痫前期（PE）发病的关键点。相关因素造成EVT内质网和线粒体功能异常，将引起细胞凋亡增加、功能损害。课题组前期研究发现，PE患者EVT中FAM134B表达升高，与其相关的内质网自噬被过度激活；内质网与线粒体之间存在“线粒体结合内质网膜（MAMs）”这一特殊结构。我们推测：EVT中FAM134B基因表达上调致内质网过度自噬，打破内质网稳态，引起Ca2+异常释放，进而通过MAMs引起线粒体Ca2+超载，诱发线粒体相关凋亡，造成EVT功能受损，胎盘浅着床，血管重铸障碍，最终导致PE。项目拟运用分子生物学、细胞生物学和基因工程等手段，在临床样本、组织模型、细胞模型和动物模型中对该假说加以验证，为子痫前期发病机制的研究开辟新的方向。

Unsuccessful vascular remodeling caused by the loss of the invasive ability of extravillous trophoblast (EVT) is the key to the pathogenesis of preeclampsia (PE). Abnormalities in endoplasmic reticulum (ER) and mitochondria will result in such cell apoptosis and function loss. Preliminary investigations of our group revealed up-regulated expression of family with sequence similarity 134, member B (FAM134B) gene, together with excessive autophagy of endoplasmic reticulum (ER); and that ER and mitochondria are adjacent to each other with mitochondria-associated endoplasmic reticulum membranes (MAMs), a special structure, in between. We hypothesis that the over-expression of FAM134B gene in EVT caused the ER over-autophagy, which breaks the homeostasis of ER and results in abnormal release of Ca2+ that lead to Ca2+ overload in mitochondria via MAMs; the latter induces mitochondria-associated apoptosis, consequently brings about the damage in EVT function, shallow placental implantation, difficulties in vascular remodeling, and eventually the onset of PE. This project aims to verify this hypothesis on the basis of clinical samples, and tissue, cellular and animal models, using techniques including molecular biology, cellular biology and gene engineering, with the hope of establishing a new research orientation for the studies on PE pathogenesis.