反式转录激活因子蛋白转导技术在缺血性脑卒中中的应用进展

The significance of the transactivator of transcription-mediated protein transduction technique in brain protection

背景蛋白转导结构域（protein transducer domain，PTD）使大分子药物可以通过血脑屏障（blood brain barrier，BBB），受到了日益广泛地关注。目的以应用最为广泛的反式转录激活因子（transactivator of transcription，TAT）蛋白转导结构域为核心，通过总结其在神经系统疾病中的作用及机制，为相关领域研究提供参考。内容TAT蛋白转导结构域是人类I型免疫缺陷病毒（human immunodeficiencv virus-1，HIV-1）的功能性结构域。目前已与红细胞生成素（erythropoietin，EPO）、胶质细胞源神经营养因子（glial cell line-derivedn eurotrophic factor，GDNF）、Nogo-A细胞外肽140（nogo extracellular peptide1-40，NEP1-40）、抗凋亡蛋白等多种功能性蛋白重组融合，不仅使其透过BBB发挥神经保护作用，还减少了药物副作用。尤其是突触后致密物蛋白-95（synapses dense protein-95，PSD-95）融合形成的TAT-NR289c可减少脑梗死容积，改善神经功能，已完成Ⅱ期临床试验。趋向TAT蛋白转导技术在神经系统疾病的治疗中具有显著优势，为临床治疗脑卒中的新药研发提供了新的方向。

Background Protein transduction domain （PTD）, a novel structure for carrying various of macromolecules through the blood-brain barrier （BBB）, have been receiving great attention in the recent years. Objective In order to provide a reference for the related fields, we summed up the neuroprotective effects and possible mechanisms of transactivator of transcription （TAT）-mediated protein transduction domain, which is the most extensively studied PTD. Content TAT -mediated protein transduction domain is a special structure of human immunodeficiency virus type I （HIV-I）. Up to now, it has been fused with erythropoietin （EPO）, glial cell line-derived neurotrophic factor （GDNF）, Nogo Extracellular Peptide 1-40 （NEP1-40） and Bcl-xL. These fusion proteins could not only pass through the BBB, but also offer neuroprotection for alleviating cerebral ischemia injury with reduced side effects. Most of all, TAT-NR2B9c, a fusion protein of TAT and synapses dense protein-95 （PSD-95）, has been proved to be efficient for reducing cerebral infarction by inhibiting neurotoxicity not only in experimental animal, but also in the phase Ⅱ clinical trial. Trend TAT-mediated protein transduction technique may offer new perspectives for future strategies in stroke therapy.