HGTD-P启动子差异结合蛋白在新生鼠缺氧缺血性脑损伤中的作用

Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe disease of nervous system, but is lack of speicific treatment till now. It is very important to explore its impairment and reparation mechanism. Our previous studies have confirmed that human growth transformation dependent protein (HGTD-P) is a key factor to promote neuronal apoptosis induced by hypoxia-ischemia, so it is an effective way to reduce neuronal apoptosis by inhibiting the expression of HGTD-P. Our pilot experiment has found that the expression of proteins binding with HGTD-P promoter is quite different, which strongly suggests that the binding-proteins play an important role in regulating the expression of HGTD-P after hypoxic-ischemic stimulus. Based on this, we predict that some up-regulation proteins binding with HGTD-P promoter regulate its transcription and promote its expression, which could aggravate neuronal apoptosis and brain damage. In this study, we try to screen and identify the binding proteins participating in the activating path of HGTD-P, to explore its function in the hypoxic-ischemic neonatal rats, in order to find a new target regulating the expression of HGTD-P, which could provide scientific clues for the treatment of HIE.

新生儿缺氧缺血性脑病（HIE）是小儿严重的神经系统疾病，但尚无特异性治疗措施，探索HIE的损伤修复机制具有重要意义。我们既往研究已证实人生长与转化依赖蛋白（HGTD-P）是促进缺氧缺血后神经元凋亡的关键分子，抑制其表达是减轻神经元凋亡的有效途径。我们的前期试验发现在缺氧缺血诱导下大鼠神经元HGTD-P启动子结合蛋白的表达存在差异，强烈提示启动子结合蛋白参与了缺氧缺血后HGTD-P表达的调控。因此我们推测在缺氧缺血条件下，某些表达上调的蛋白通过与HGTD-P启动子结合，调控HGTD-P的转录，促进HGTD-P的表达，诱导神经元的凋亡，从而加重缺氧缺血性脑损伤。本项目拟筛选鉴定参与HGTD-P通路活化的DNA结合蛋白，研究应用启动子结合蛋白抑制策略减轻缺氧缺血性脑损伤的可行性，探讨其在新生大鼠缺氧缺血动物模型中的效应，以期发现调控HGTD-P表达的新靶点，为临床治疗HIE提供科学依据。

新生儿缺氧缺血性脑病（HIE）是小儿严重的神经系统疾病，但尚无特异性治疗措施，探索HIE的损伤修复机制具有重要意义。我们既往研究已证实人生长与转化依赖蛋白（HGTDP）是促进缺氧缺血后神经元凋亡的关键分子，抑制其表达是减轻神经元凋亡的有效途径。本研究中，我们构建了体外培养的神经元氧糖剥夺（OGD） 模型及新生大鼠缺氧缺血脑损伤（HIBD ）动物模型，筛选鉴定了缺氧缺血诱导上调HGTD-P 蛋白表达的差异启动子结合蛋白NF-κB和HIF-1α，并结合蛋白芯片寻找到参与HGTD-P调控的新靶点Ｈｓｐ９０，发现Ｈｓｐ９０活性抑制剂可减少ＨＧＴＤ－Ｐ和Ｈｓｐ９０的结合，阻止神经元凋亡,减轻缺氧缺血诱导的脑损伤， 为以HGTD-P为靶点的新生儿脑损伤治疗提供了新策略。