FAM3A在胎儿窘迫中神经保护及对内质网Ca2+稳态影响机制研究

Fetal distress is a common disease in pregnancy, leads to serious neonatal brain damage or neonatal death, the dysregulation of endoplasmic reticulum calcium homeostasis is a key of the pathological process of nerve cell damage. Our recent research data found that that FAM3A can protect the HT22 cells by the PI3K/Akt signaling pathway which was mediated calcium ions. In addition ,FAM3A can play the neuroprotection on the HT22 cells from the ER stress. We speculate that FAM3A may affect the ER calcium ions, thereby affecting the extent of nerve cell damage. In this research, we plan to investigate the neuroprotection of FAM3A, and clarify that FAM3A play the role through the regulation of endoplasmic reticulum calcium homeostasis using in vitro, in vivo and gene silencing and overexpression by lentivirus transfection in fetal distress. We also propose to reveal the mechanism of neuroprotective effects and endoplasmic reticulum calcium homeostasis regulation of FAM3A in fetal distress, which could potentially facilitate novel therapeutic targets in fetal distress.

胎儿窘迫是一种常见的妊娠期疾病，严重时会致新生儿永久性脑损伤甚至死亡，其中内质网Ca2+稳态失衡是神经细胞损伤的关键病理过程。课题组前期发现：1）H2O2引起HT22神经细胞损伤过程中，FAM3A 可通过Ca2+介导的PI3K/Akt 通路发挥神经保护作用；2）FAM3A在内质网应激介导的HT22神经细胞损伤过程中发挥保护作用。我们推测FAM3A 很可能会对内质网Ca2+稳态产生影响，进而影响神经细胞的损伤程度。本项目拟在此基础上通过在体、离体及慢病毒干扰关键分子的过表达、沉默等多种技术阐明FAM3A在胎儿窘迫模型小鼠胚胎脑缺氧缺血损伤后的神经保护作用，继而阐明其通过调节内质网Ca2+稳态发挥作用的机制，有望揭示FAM3A在胎儿窘迫胚胎脑缺氧缺血性损伤过程中的神经保护机制，为探索胎儿窘迫治疗新靶点提供理论依据。

胎儿窘迫是一种常见妊娠期疾病，严重时会致新生儿永久性脑损伤甚至死亡，其中内质网Ca2+稳态失衡是神经细胞损伤的关键病理过程。本项目通过在体、离体及慢病毒干扰关键分子的过表达、沉默等多种技术阐明FAM3A在胎儿窘迫模型小鼠胚胎脑缺氧缺血损伤后的神经保护作用，发现胎儿窘迫后，新生小鼠脑组织内 FAM3A含量显著下降，通过对 FAM3A进行过表达或者沉默，经FAM3A过表达的小鼠从脑含水量、神经运动功能学、脑损伤保护等方面均优于胎儿窘迫组。在细胞中FAM3A过度表达减弱了缺血缺氧对细胞的损害。FAM3A的这些作用可能依赖于其对细胞内钙稳态的调节，FAM3A可能不仅通过抑制mGluR1/5的表达抑制ER-Ca2+的释放，而且通过干扰STIM1-Orai1复合物减弱SOCE介导的Ca2+内流，FM3A可能通过这些途径对缺氧缺血性损伤起到神经保护的作用，这些研究结果可能为探索胎儿窘迫治疗新靶点提供一定理论依据。