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Analysis of Thymidine phosphorylase- Uridine phosphorylase double knockout mice

胸苷磷酸化酶-尿苷磷酸化酶双敲除小鼠分析

基本信息

批准号：
13670149
负责人：
HARAGUCHI Misako
金额：
$ 2.62万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Thymidine phosphorylase (TP) is an enzyme involved in the reversible conversion of thymidine to thymine. In cancer patients and tumor-bearing animals, plasma TP level is elevated, and its expression in various solid tumors is higher than in the adjacent non-neoplastic tissues. Both TP itself and the degradation product of thymidine, 2-deoxy-D-ribose, had chemotactic and angiogenic activities, and the enzymatic activity of TP was required for its angiogenic activity. TP was expressed mainly at the invasive edges of tumors and TP expression was associated with the extent of invasion of gastric and colorectal carcinoma.TP expression was also elevated in chronically inflamed tissues. TNF alpha and IFN gamma are reported to induce TP expression. To confirm the physiological role of TP, we generated mice deficient in TP gene (TPKO). TPKO mice showed an increased resistance to infection by Listeria monocytogenes. Splenic and hepatic bacterial loads 3 days after inoculation were decreased about 1 logs in TPKO. TPKO mice displays increase Interferon gamma level in plasma whereas less level of IL-10. The liver cells and spleen cells were obtained from infected mice, and cultured. The IL-10 levels in the conditioned media of the cells from TPKO mice were significantly less than those from wild-type mice. IL-10 is known to be a potent anti-inflammatory cytokine, and is suggested to reduce the function of tumor infiltrating lymphocytes and contributes the tumor growth. Therefore, we tried to test the role of TP in the escape of tumors from immune systems. Age and sex matched mice (wild-type and TP-/-) were injected i.p. with 1x10^6 of EL-4 cells. Two week after the challenge with EL-4 cells, the increase in volumes of ascites and the growth of EL-4 cells are significantly less in TPKO mice than in wild-type mice. Thus, TP may allow the escape of tumors from immune destruction and contribute the tumor growth.

胸苷磷酸化酶（TP）是一种参与胸苷可逆转化为胸腺嘧啶的酶。在癌症患者和荷瘤动物中，血浆TP水平升高，其在各种实体瘤中的表达高于邻近的非肿瘤组织。 TP本身和胸苷的降解产物2-脱氧-D-核糖均具有趋化和血管生成活性，并且TP的酶活性是其血管生成活性所必需的。 TP主要表达于肿瘤的浸润边缘，TP表达与胃癌和结直肠癌的浸润程度相关。在慢性炎症组织中TP表达也升高。据报道 TNF α 和 IFN γ 可诱导 TP 表达。为了证实TP的生理作用，我们培育了TP基因缺陷型小鼠（TPKO）。 TPKO 小鼠表现出对单核细胞增生李斯特氏菌感染的抵抗力增强。 TPKO 中接种后 3 天，脾脏和肝脏细菌负荷减少约 1 个对数。 TPKO 小鼠血浆中干扰素 γ 水平升高，而 IL-10 水平降低。从感染的小鼠中获取肝细胞和脾细胞并进行培养。 TPKO小鼠细胞条件培养基中IL-10的水平显着低于野生型小鼠。 IL-10 被认为是一种有效的抗炎细胞因子，并被认为可以降低肿瘤浸润淋巴细胞的功能并促进肿瘤生长。因此，我们试图测试TP在肿瘤逃离免疫系统中的作用。对年龄和性别匹配的小鼠（野生型和 TP-/-）进行腹腔注射。具有 1x10^6 EL-4 细胞。 EL-4细胞攻击两周后，TPKO小鼠腹水量的增加和EL-4细胞的生长明显少于野生型小鼠。因此，TP可能使肿瘤逃避免疫破坏并促进肿瘤生长。