FUNCTION & REGULATION OF SPASMOLYTIC POLYPEPTIDE/TFF2

描述(摘自申请者摘要)：解痉多肽 (SP/TFF2)是三叶因子家族中的一个成员，具体表达在 胃粘液颈细胞，一种鲜为人知的胃细胞谱系 被认为代表了胃腺癌的起源细胞。上一首 研究表明，SP表达细胞在胃局部上调。 损伤，SP可能在粘膜修复中发挥作用。从这里开始工作 使用H.Felis-小鼠模型的实验室已经证明了 SP表达细胞与增殖前体的关系 血统，研究人员已经证明依赖于幽门螺杆菌 表达SP的细胞的放大与顶叶细胞的减少是平行的 细胞，随后是胃癌的发展。这群人有 产生了一个SP基因敲除小鼠，以及他们关于SP在 这些初步发现加强了胃的分化 壁细胞数量增加的小鼠。AGS中瞬时转基因的研究 SP启动子-荧光素酶构建的胃癌细胞已导致 三叶草/生长因子反应元件和胃的鉴定 细胞特异性基础增强剂。综上所述，这些观察结果 提出了这样的假设：SP基因代表了 胃粘膜中的增殖前体(干细胞)：它是 受三叶肽和幽门螺杆菌通过特定的 顺式作用元件：SP在粘膜再生和修复中的作用 通过对胃上皮细胞分化的调控。他们提议研究一下 SP的功能和调控通过以下目标：(1)确定 胃细胞特异性SP基因表达的分子基础。他们会 描述三叶反应元件和细胞特定元件在 人和小鼠的SP启动子，并探索SP表达的可能调节 由幽门螺杆菌在体外培养。(2)鉴定胃细胞特异性启动子元件 通过在转基因小鼠体内表达。他们将产生MSP-GFP和 MSP-β-Gal转基因株系的建立及转基因表达变化分析 小鼠胃癌模型对幽门螺杆菌的反应。(3)调查 利用靶基因产生的SP缺陷小鼠研究SP的功能 颠覆。胃分化的变化将被量化，而SP 在NSAID和H.Felis模型中测试的缺陷小鼠。总体而言，这些研究 将利用胃癌模型来探讨其功能和调控。 SP，并可能为进一步了解颈部粘液细胞的生物学特性提供依据。

DESCRIPTION (Adapted from the Applicant's Abstract): Spasmolytic polypeptide (SP/TFF2) is a member of the trefoil factor family specifically expressed in gastric mucous neck cells, a poorly understood stomach cell lineage that is believed to represent the cell of origin for gastric adenocarcinoma. Previous studies have shown that SP-expressing cells are upregulated at sites of gastric injury, and that SP may play a role in mucosal repair. Work from this laboratory employing a H. felis-mouse model has demonstrated a close relationship between SP-expressing cells and the proliferative precursor lineage, and the investigator has shown that Helicobacter-dependent amplification of the SP-expressing cells is paralleled by a decline in parietal cells, followed later by the development of gastric cancer. This group has generated an SP knockout mouse, and their hypothesis regarding a role for SP in gastric differentiation has been strengthened by preliminary findings in these mice of increased parietal cell number. Transient transfection studies in AGS gastric cancer cells of SP promoter-luciferase constructs have led to the identification of trefoil/growth factor response elements, as well as gastric cell-specific basal enhancers. Taken together, these observations have suggested the hypotheses that: the SP gene represents a marker for proliferating precursor (stem) cells in the gastric mucosa: that it is regulated by trefoil peptides and Helicobacter pylori through a specific cis-acting element: and that SP functions in mucosal regeneration and repair through modulation of gastric epithelial differentiation. They propose to study the function and regulation of SP through the following aims: (1) determine the molecular basis of gastric cell-specific SP gene expression. They will characterize the trefoil response element and cell specific elements in the human and murine SP promoters, and explore possible regulation of SP expression by H. pylori in vitro. (2) Characterize gastric cell-specific promoter elements through in vivo expression in transgenic mice. They will generate mSP-GFP and mSP-beta-Gal transgenic lines and analyze changes in transgene expression in response to Helicobacter in gastric cancer mouse models. (3) Investigate the function of SP utilizing the SP deficient mice generated through targeted gene disruption. Changes in gastric differentiation will be quantitated, and the SP deficient mice tested in both NSAID and H. felis models. Overall, these studies will utilize gastric cancer models to explore the function and regulation of SP, and may provide further insight into the biology of mucous neck cells.