Role of SV40 in Salivary Gland Tumorigenesis

描述：(申请人提供)恶性唾液腺肿瘤 异质的。多种多样的生物行为，罕见和高风险 复发使这些肿瘤的临床治疗具有挑战性。《长河》 本项目的学期目标是：1)了解早期分子变化 发生在涎腺肿瘤发生中；2)确定猿猴的作用 病毒40(SV40)小T抗原(T-Ag)在涎腺肿瘤发生中的作用 为了建立一个动物模型，可以用来研究 糖基转移酶在涎腺肿瘤发生和转移中的作用一个 涎腺肿瘤形成的转基因小鼠模型的数量已经被 用于分析恶性组织中的分子变化。过度表达 多瘤中T抗原(PyVmT)或猴病毒40(SV40)大 小鼠唾液腺中的T抗原可导致唾液腺的增殖和肿瘤形成。 本项目的具体目标是：1)研究小麦的分子标记 MMTV/PyVmT小鼠增生性病变中的肿瘤发生。一种组合 将进行显微镜、形态测量和免疫组织化学分析 以获取有关转基因表达、上皮细胞增殖的信息 分化程度、微血管密度、糖基化改变和间质 腺体的变化。2)探讨唾液中SV40T-Ag的作用 腺体肿瘤的发生。单拷贝靶向载体，含SV40 TT-Ag或 T-Ag单独在腮腺分泌蛋白启动子的控制下 通过电穿孔进入胚胎干细胞(ES)而进入小鼠生殖系 细胞。同源重组事件阳性的ES细胞将是 注射到囊胚中产生基因靶向的小鼠。老鼠们将会是 回到C57BL/6背景，检查T-AG和T-AG 利用荧光蛋白记者进行表达。分子变化分析 发生在唾液腺肿瘤发生过程中可能会导致 治疗恶性疾病的治疗剂。

DESCRIPTION: (provided by applicant) Malignant salivary gland tumors are highly heterogeneous. The varied biologic behavior, infrequency and high risk of recurrence makes the clinical management of these tumors challenging. The long term objectives of this project are: 1) to understand early molecular changes occurring in salivary gland tumorigenesis; 2) to determine the role of simian virus 40 (SV40) small t antigen (t-ag) in salivary gland tumorigenesis; and 3) to create an animal model which can be utilized to examine the role of glycosyltransferase enzymes in salivary gland tumorigenesis and metastasis. A number of transgenic mouse models in which salivary gland tumors form have been used to analyze molecular changes in malignant tissues. Overexpression of either the polyoma middle T antigen (PyVmT) or the simian virus 40 (SV40) large T antigen in murine salivary glands results in hyperplasia and tumor formation. The specific aims of this project are: 1) To examine molecular markers of tumorigenesis in hyperplastic lesions of MMTV/PyVmT mice. A combination of microscopic, morphometric and immunohistochemical analysis will be carried out to obtain information about transgene expression, epithelial cell proliferation and differentiation, microvascular density, glycosylation changes and stromal alterations in the glands. 2) To investigate the role of SV40 t-ag in salivary gland tumorigenesis. Single copy targeting vectors containing the SV40 Tt-ag or T-ag alone under the control of the parotid secretory protein promoter will be knocked in to the mouse germline by electroporation into embryonic stem (ES) cells. ES cells positive for the homologous recombination event will be injected into blastocysts to generate gene targeted mice. The mice will be backcrossed into the C57Bl/6 background and examined for t-ag and T-ag expression using fluorescent protein reporters. Analysis of molecular changes occurring during salivary gland tumorigenesis may lead to the development of therapeutic agents for the treatment of malignant disease.