FUNCTION OF A NOVEL TYROSINE KINASE IN THE INTESTINE

描述：研究者的既往研究确定了一种新的 酪氨酸激酶，Sik，在肠上皮细胞中表达， 小鼠小肠和大肠中的终末分化。 的 研究人员还表明，这种激酶的人类同源物是已知的 先前在转移性乳腺肿瘤（Brk）中鉴定的蛋白质。 基于 这些研究，目前项目的目标是确定生物 Sik/Brk的功能，并确定Brk表达是否是 在结肠癌的发展过程中发生了改变。 四个具体目标是 提出了 第一，Brk的表达和/或激活在肿瘤细胞的部分中， 将人结肠腺瘤和癌与正常组织进行比较。 在 第二，用各种Sik构建体转染细胞系模型 并检查对增殖或分化的影响。 第三个目标， 转基因方法将用于消除小鼠中的Sik功能 肠，使用iFABP靶向的显性阴性突变体 启动子 最后，申请人将审查敲除的效果 小鼠中的Sik表达。 总的来说，这些研究希望澄清 新的上皮细胞特异性酪氨酸激酶的生物学作用， Sik/Brk，在正常肠上皮细胞中以及在 肠道恶性肿瘤

DESCRIPTION: Previous studies of the investigator identified a novel tyrosine kinase, Sik, expressed in intestinal epithelial cells undergoing terminal differentiation in the small and large intestines of mice. The investigator also showed that the human homologue of this kinase is a known protein previously identified in a metastatic breast tumor (Brk). Based on these studies, the goal of the current project is to identify the biological functions of Sik/Brk, and also to determine whether Brk expression is altered during the progression of colon cancer. Four specific aims are proposed. In the first, expression and/or activation of Brk in sections of human colon adenomas and carcinomas will be compared to normal tissues. In the second, cell line models will be transfected with various Sik constructs and effects on proliferation or differentiation examined. In the third aim, transgenic approaches will be used to ablate Sik function in the mouse intestine, using a dominant negative mutant targeted using the iFABP promoter. Finally, the applicant will examine the effect of knocking out Sik expression in mice. Overall, the studies are hoped to clarify the biological role of the novel epithelial cell specific tyrosine kinase, Sik/Brk, in normal intestinal epithelial cells as well as in the progression of intestinal malignancies.