FUNCTION & REGULATION OF SPASMOLYTIC POLYPEPTIDE/TFF2

功能

• 批准号: 6517987
• 负责人: Timothy Cragin Wang
• 金额: $ 23.3万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517987
• 关键词: Helicobacter; cell differentiation; cell line; cell proliferation; gastric mucosa; gene expression; gene targeting; genetic promoter element; genetic regulatory element; genetically modified animals; growth factor; laboratory mouse; protein structure function; regeneration; stem cells

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.

说明书（改编自申请人的摘要）：痉挛多肽 (SP/TFF 2）是三叶因子家族的成员，其特异性表达于 胃粘液颈细胞是一种了解甚少的胃细胞谱系， 被认为代表胃腺癌的起源细胞。先前 研究表明，表达SP的细胞在胃粘膜的某些部位上调， SP可能在粘膜修复中起作用。从这个开始工作 实验室采用H.猫鼠模型已经证明了一个接近 SP表达细胞与增殖前体的关系 研究人员已经表明，依赖于螺旋杆菌的 SP表达细胞的扩增被壁细胞的减少所抑制， 细胞，其次是胃癌的发展。这一群体 产生了一个SP基因敲除小鼠，他们的假设，SP的作用， 这些初步发现加强了胃的分化， 小鼠的壁细胞数量增加。AGS中的瞬时转染研究 SP启动子-荧光素酶构建体的胃癌细胞导致了 三叶草/生长因子反应元件的鉴定，以及胃 细胞特异性基础增强子。综合起来，这些观察结果 提出了这样的假设：SP基因代表了 增殖前体（干）细胞在胃粘膜：这是 三叶肽和幽门螺杆菌通过一种特异性 顺式作用元件：SP在粘膜再生和修复中起作用 通过调节胃上皮分化。他们提议研究 通过以下目标来实现SP的功能和调节：（1）确定 胃细胞特异性SP基因表达的分子基础。他们将 表征三叶响应元件和细胞特异性元件， 人和鼠SP启动子，并探讨可能的调节SP表达 由H. pylori的体外研究。(2)表征胃细胞特异性启动子元件 通过在转基因小鼠体内表达。它们将产生mSP-GFP， mSP-beta-Gal转基因系，并分析转基因表达的变化。 胃癌小鼠模型中对螺杆菌的反应。(3)探讨 利用SP功能通过靶向基因产生的SP缺陷小鼠 破坏胃分化的变化将被定量，并且SP 在NSAID和H.猫模型。总的来说，这些研究 将利用胃癌模型，探讨 SP，并可能提供进一步了解粘液颈细胞的生物学。