Regulation and Analysis of Excitatory Neuronal Cell Death by Protein Transduction Therapy

随着人类基因组的阐明，与基因转录和翻译的蛋白质产物的结构和功能相关的基因组数据的详尽分析已经迅速进展。将蛋白质及其功能域或抑制肽直接递送到神经元中是治疗兴奋性神经元细胞死亡和相关信号转导的理想方法。然而，蛋白质通常被截留在细胞质中的大胞饮体内。因此，需要高剂量浓度的蛋白质才能有效发挥作用。为了克服这个问题，在这个项目中，聚精氨酸与流感病毒血凝素-2亚基（HA 2）的NH（2）-末端结构域连接，HA 2是一种pH依赖性融合肽，其在低pH水平下诱导膜溶解。我们还设计了与蛋白转导结构域融合的钙蛋白酶和TRPM 7抑制肽，并检测了其对缺血性神经细胞死亡的保护作用。这些设计的肽显着保护缺血性细胞死亡。这些数据清楚地表明蛋白转导系统是治疗缺血性神经细胞死亡有用方法。

With the elucidation of the human genome, exhaustive analysis of genomic data related to gene transcription and the structure and function of translated protein products has progressed rapidly. Delivery of proteins and their functional domains or inhibitory peptides directly into the neuron is ideal to treat excitatory neuronal cell death and related signal transduction s.However, the protein is often entrapped inside macropinosomes in the cytoplasm. Therefore, high dose concentrations of the protein are needed for it to function effectively. To overcome this problem, in this project, polyarginine was linked with the NH(2)-terminal domain of influenza virus hemagglutinin-2 subunit (HA2), which is a pH-dependent fusogenic peptide that induces the lysis of membranes at low pH levels. We also designed the calpain and TRPM7 inhibitory peptide fused with protein transduction domain and examined the protective effect for ischemic neuronal cell death. These designed peptides were significantly protected against ischemic cell death. These data clearly show that protein transduction system is useful method for treat ischemic neuronal cell death.