Vaccination therapy against malignant glioma using apoptosis-inducing genes

使用细胞凋亡诱导基因针对恶性神经胶质瘤的疫苗治疗

• 批准号: 07407038
• 负责人: ASAI Akio
• 金额: $ 23.23万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07407038/
• 关键词: Apoptosis; glioma; calcineurin; proteasome; ワクチン療法; differential display PCR

We cloned several genes whose expression level increase or decrease along with the progression of myc-induced apoptosis in glioma cells by differential display PCR method. One of the genes was calmodulin. Therefore, in this study, we hypothesized that calciummediated signal transduction may be involved in apoptosis and the activation of immunogenicity in malignant glioma cells and tried to investigate their molecular mechanism by confirming the hypothesis. Although we have not reached the final goal, we have found the following several important findingsregarding molecular mechanisms of apoptosis : (1) the expression level of calcineurin is extremely high in the brain as was reported ; (2)when the activity of calcineurin increases, the activity of proteasome decreases ; (3)when the proteasome activity was perturbed by inhibitors, apoptosis is induced in the cells ; (4)as a result, the cells with high calcineurin activity are vulnerable to apoptosis. These results may elucidate that hippocampal CA1 neurons with high calcineurin expression are vulnerable to delayd neuronal death induced by transient iscemia although these results are not exclusive to neural cells. It is probable that gliomaspecific mechanisms such as sctivation of tumor-immunogenicity are located downstream of the proteasome function. It is extremely important to clarify the function of proteasome in apoptosis and activation of tumor-immunogenicity and such a project is in progress.

我们用差异显示PCR方法克隆了几个随着myc诱导胶质瘤细胞凋亡进程而表达水平沿着升高或降低的基因。其中一个基因是钙调素。因此，本研究假设钙离子介导的信号转导可能参与了恶性胶质瘤细胞的凋亡和免疫原性的激活，并试图通过证实这一假设来探讨其分子机制。虽然我们还没有达到最终的目的，但我们发现了以下几个重要的凋亡分子机制的发现：（1）钙调磷酸酶在脑中的表达水平极高，（2）当钙调磷酸酶活性增加时，蛋白酶体活性降低，（3）当蛋白酶体活性受到抑制剂的干扰时，细胞凋亡被诱导，（4）当钙调磷酸酶活性降低时，细胞凋亡被诱导。（4）钙调神经磷酸酶活性高的细胞易发生凋亡。这些结果可能说明，高表达钙调神经磷酸酶的海马CA1区神经元易受短暂性缺血诱导的延迟性神经元死亡，尽管这些结果并不限于神经细胞。胶质瘤特异性机制如肿瘤免疫原性的激活可能位于蛋白酶体功能的下游。阐明蛋白酶体在细胞凋亡和激活肿瘤免疫原性中的作用是非常重要的，这方面的研究正在进行中。

项目成果

浅井昭雄: "グリオーマ細胞におけるアポトーシスと免疫原性変化の誘導" 脳神経外科. 23. 7-15 (1995)

Akio Asai：“神经胶质瘤细胞凋亡和免疫原性变化的诱导”《神经外科》23. 7-15 (1995)。

Asai A, et al.: "Abundant expression of translation initiation factor EIF-4E in post-meiotic germ cells of the rat testis." Lab Invest. 72. 890-898 (1995)

Asai A 等人：“翻译起始因子 EIF-4E 在大鼠睾丸减数分裂后生殖细胞中大量表达。”

Asai A, et al.: "Caspase-dependent apoptosis of COS-7 cells induced by Bax overexpression:differential effects of Bcl-2 and Bcl-xL on Bax-induced caspase activation" Oncogene. 15. 1471-1480 (1997)

Asai A 等人：“Bax 过表达诱导的 COS-7 细胞的 Caspase 依赖性凋亡：Bcl-2 和 Bcl-xL 对 Bax 诱导的 caspase 激活的差异作用”Oncogene。

Asai A,et al.: "s-Myc acts as a transcriptional activator and its sequence-specific DNA binding is required for induction of programd cell death in glioma cells." Cell Death Differ. 2. 123-131 (1995)

Asai A 等人：“s-Myc 充当转录激活剂，其序列特异性 DNA 结合是诱导神经胶质瘤细胞程序性细胞死亡所必需的。”

Asai A, et al.: "s-Myc acts as a transcriptional activator and its sequence-specific DNA binding is required for induction of programmed cell death in glioma cells." Cell Death Differ. 2. 123-131 (1995)

Asai A 等人：“s-Myc 充当转录激活剂，其序列特异性 DNA 结合是诱导神经胶质瘤细胞程序性细胞死亡所必需的。”