人Vasostatin及其融合人TRAIL的克隆表达与生物学活性研究

发布时间：2018-01-23 19:44

本文关键词： 新生血管抑制剂 Vasostation TRAIL 重组表达抗肿瘤融合蛋白　出处：《第二军医大学》2005年硕士论文　论文类型：学位论文

【摘要】：新生血管的形成(angiogenesis)是从已有血管生成新血管的重要生理和病理过程,其可发生在胚胎形成、子宫内膜周期性变化、伤口愈合和肿瘤生长等环节。新生血管形成是一个复杂的过程,受到一系列正负生长因子的调控。一旦这些正负调控因子失去平衡,就可能造成不正常的新生血管形成,导致肿瘤的生长转移、心肌梗塞和糖尿病等疾病。与正常细胞一样,肿瘤细胞的代谢和营养需要从血液中获取氧气和养料,运走代谢产生的物质。如果没有这些充足的营养供应,一个肿瘤块就只能长到2mm~3那么大。血管生成除了供给肿瘤生长必需的养分外,也是肿瘤转移的必要的条件之一,肿瘤细胞进入血液循环从而向其他组织器官浸润转移。如果抑制新生血管形成,肿瘤细胞将发生凋亡或坏死。这就为抗肿瘤治疗提供了一条新思路,目前临床上已有多种抑制新生血管的药物用于抗肿瘤治疗。 Vasostatin是最近发现的一个血管生成抑制因子,最初是从经EB病毒转化的B细胞系VDS-O的培养上清液中提纯,是钙网蛋白(calreticulin)的N-端1～180个氨基酸组成的结构域片段。Vasostatin可有效且专一的抑制内皮细胞的增生,使新生血管无法生成,进而抑制肿瘤的生长。将Vasostatin注射于无胸腺小鼠中,可明显抑制Burkitt淋巴瘤和人结肠癌的生长。Vasostatin通过抑制血管内皮细胞的增殖、迁移和抑制新生血管的形成,从而抑制肿瘤生长。当前的研究表明Vasostatin具有抗肿瘤效果明显、毒副作用低等特点,但尚不知Vasostatin片段是通过何种途径作用于细胞,近期的研究表明可能与细胞表面因子Laminin有关。 1995年,国外报道从人表达标签序列文库(expressed sequence tag,EST)中筛选到一种编码抗肿瘤蛋白质的基因,该基因编码的蛋白质称为肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor-related apoptosis-inducing ligand,TRAIL),又称凋亡素2配体(apoptotin-2 ligand,简称Apo-2L),是肿瘤坏死因子(tumornecrosis factor,TNF)家族成员之一,其通过启动细胞固有的凋亡程序,可有效地诱导肿瘤和转化细胞凋亡,而对正常细胞无影响。人TRAIL基因的编码序列有843个核苷酸,编码的蛋白质TRAIL由281个氨基酸组成。研究表明TRAIL是典型
[Abstract]:Angiogenesis is an important physiological and pathological process of angiogenesis from existing blood vessels. It may occur in embryo formation and endometrial periodic changes. Wound healing and tumor growth. Neovascularization is a complex process regulated by a series of positive and negative growth factors. It can cause abnormal angiogenesis, leading to tumor growth and metastasis, myocardial infarction and diabetes. Just like normal cells, the metabolism and nutrition of tumor cells require oxygen and nutrients from the blood. Remove metabolites. Without these sufficient nutrients, a tumor can only grow to the size of 2 mm. Angiogenesis provides only the nutrients necessary for the growth of the tumor. It is also a necessary condition for tumor metastasis, when tumor cells enter the blood circulation to infiltrate and metastasize to other tissues and organs, if angiogenesis is inhibited. Apoptosis or necrosis will occur in tumor cells, which provides a new idea for anti-tumor therapy. At present, there are many anti-angiogenic drugs used in anti-tumor therapy. Vasostatin is a recently discovered angiogenesis inhibitor which was initially purified from the supernatant of B cell line VDS-O transformed by EB virus. Vasostatin, a 1-180 amino acid domain of calreticulin (calreticulin), can effectively and specifically inhibit the proliferation of endothelial cells. Vasostatin was injected into thymus-free mice by preventing neovascularization, which in turn inhibited tumor growth. Vasostatin can significantly inhibit the growth of Burkitt lymphoma and human colon cancer. Vasostatin inhibits the proliferation, migration and angiogenesis of vascular endothelial cells. In order to inhibit tumor growth. Current studies show that Vasostatin has obvious anti-tumor effect, low toxicity and other characteristics. However, it is not known how the Vasostatin fragment acts on cells, and recent studies have shown that it may be related to the cell surface factor Laminin. In 1995, a gene encoding antitumor protein was screened from human expression tag library expressed sequence tagESTs. The protein encoded by the gene is called tumor necrosis factor-related apoptosis-inducing ligand (TNF- related apoptosis-inducing ligand). Tumor necrosis factor-related apoptosis-inducing ligand. Trail, also known as apoptotin-2 ligand (Apo-2L). TNFs is a member of the tumor necrosis factor TNFs family, which initiates the inherent apoptosis process of the cells. It can effectively induce apoptosis of tumor and transformed cells, but has no effect on normal cells. The coding sequence of human TRAIL gene has 843 nucleotides. The protein TRAIL is composed of 281 amino acids. Studies show that TRAIL is a typical protein.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2005
【分类号】：R346

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