Notch Regulation of Gastric Antral Stem Cells

胃窦干细胞的Notch调节

• 批准号: 8202416
• 负责人: Elise Hibdon
• 金额: $ 4.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202416
• 关键词: Address; Adenocarcinoma; Adult; Affect; Antral; Apoptosis; Apoptotic; Build-it; Cancer Biology; Cancer Etiology; Cancer cell line; Cancerous; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular biology; Cessation of life; Chief Cell; Colon Carcinoma; Development; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Equilibrium; Funding; Gastric Adenocarcinoma; Gastric Tissue; Gastrins; Genetic; Genetic Models; Genetically Engineered Mouse; Gland; Growth; Homeostasis; Human; Intrinsic factor; Laboratories; Maintenance; Malignant Neoplasms; Modeling; Mouse Strains; Mus; Mutation; Normal tissue morphology; Notch Signaling Pathway; Pathway interactions; Play; Population; Positioning Attribute; Pyloric antrum; Regulation; Reporter; Request for Applications; Role; Rosa; Second Primary Cancers; Signal Pathway; Signal Transduction; Solid Neoplasm; Stem cells; Stomach; Stomach Neoplasms; Testing; Tissues; Training; adult stem cell; base; cancer cell; cancer stem cell; career; caspase-3; cell growth; experience; gamma secretase; gastrointestinal; in vivo; inhibitor/antagonist; malignant breast neoplasm; malignant stomach neoplasm; mortality; mouse model; neoplastic cell; notch protein; post-doctoral training; promoter; recombinase; stem; theories; therapy design; tool; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): This application requests funds to support the postdoctoral training of Dr. Elise Demitrack in the field of gastric stem cells, epithelial cell homeostasis and gastric cancer biology. Cancer cell proliferation and tumor progression are affected by fundamental signaling pathways that regulate both normal tissue homeostasis and tumor growth. This proposal focuses on the Notch signaling pathway, which is known to regulate cellular processes such as stem/progenitor cell proliferation, cell survival/apoptosis and cell differentiation in several tissues, yet has not been described for the stomach. My preliminary studies in mouse models and cultured human gastric cancer cell lines demonstrate that Notch regulates gastric epithelial cell proliferation and differentiation. Moreover, analysis of the recently characterized gastric antral stem cell marker Lgr5 showed a marked decrease in expression in mice with Notch signaling inhibited, suggesting that Notch is critical for maintenance of stem cells in the stomach antrum. This proposal will test the following hypothesis: Notch signaling supports the proliferation and survival of gastric stem cells as well as proliferation of gastric cancer cells. To address this hypothesis, pharmacologic and genetic tools will be used to manipulate Notch pathway components in antral epithelial cells. Mouse strains expressing Cre recombinase driven by lineage specific gastric promoters will be crossed with genetic models of Notch activation or Notch disruption to study how Notch signaling regulates gastric epithelial stem cell survival, proliferation and lineage commitment. Analysis of Notch in gastric tumors will take advantage of established human gastric cancer cell lines, as well as the gastrin- deficient mouse model previously generated by the Samuelson laboratory, which spontaneously develops antral adenocarcinomas. Two specific aims are proposed: (1) Test the hypothesis that gastric antral stem cells are regulated by Notch signaling to maintain tissue homeostasis, through (1A) direct targeting of the Lgr5-positive antral stem cell and/or (1B) through regulation of antral epithelial cell fate; (2) Test the hypothesis that antral tumors are sustained through Notch-regulated proliferation of Lgr5-expressing stem cells, by (2A) performing lineage tracing of antral tumors in gastrin-deficient mice and (2B) determining the role of Notch for tumor growth in mouse models and human gastric cancer cells. Together, these studies will provide an excellent training experience in basic signaling pathways regulating gastric cancer to position the applicant for a career in gastric cancer biology. PUBLIC HEALTH RELEVANCE: Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related mortality worldwide. Because the Notch signaling pathway has been shown to play a role in solid tumor development in breast and colon cancers, we postulate that Notch activity may also regulate gastric cancer cell proliferation. This project will determine how Notch activity regulates the gastric antral stem cell, as well as gastric cancer stem cells in the gastrin-deficient mouse model, which develops spontaneous antral tumors.

描述（由申请人提供）：本申请要求资金支持Elise Demitrack博士在胃干细胞，上皮细胞稳态和胃癌生物学领域的博士后培训。癌细胞增殖和肿瘤进展受到调节正常组织稳态和肿瘤生长的基本信号传导途径的影响。该提议集中于Notch信号传导途径，已知其调节细胞过程，如干细胞/祖细胞增殖、细胞存活/凋亡和几种组织中的细胞分化，但尚未描述胃。我在小鼠模型和培养的人胃癌细胞系中的初步研究表明，Notch调节胃上皮细胞的增殖和分化。此外，对最近表征的胃窦干细胞标记物Lgr 5的分析显示，在Notch信号传导被抑制的小鼠中，表达显著降低，这表明Notch对于维持胃窦中的干细胞至关重要。本研究将验证以下假设：Notch信号支持胃干细胞的增殖和存活，以及胃癌细胞的增殖。为了解决这一假设，药理学和遗传学工具将被用来操纵胃窦上皮细胞中的Notch途径成分。表达由谱系特异性胃启动子驱动的Cre重组酶的小鼠品系将与Notch激活或Notch破坏的遗传模型杂交，以研究Notch信号传导如何调节胃上皮干细胞存活、增殖和谱系定型。Notch在胃肿瘤中的分析将利用已建立的人胃癌细胞系，以及由Samuelson实验室先前产生的胃泌素缺陷小鼠模型，其自发地发展胃窦腺癌。提出了两个具体目标：（1）通过（1A）直接靶向Lgr 5阳性胃窦干细胞和/或（1B）通过调节胃窦上皮细胞命运来验证胃窦干细胞受Notch信号调节以维持组织稳态的假设;（2）检验胃窦肿瘤通过Notch调节的表达Lgr 5的干细胞增殖而维持的假设，通过（2A）在缺乏胃泌素的小鼠中进行胃窦肿瘤的谱系追踪和（2B）确定Notch在小鼠模型和人胃癌细胞中对肿瘤生长的作用。总之，这些研究将提供一个很好的培训经验，在基本的信号通路调节胃癌定位申请人在胃癌生物学的职业生涯。 公共卫生相关性：胃癌是全球第四大常见癌症，也是癌症相关死亡的第二大原因。由于Notch信号通路已被证明在乳腺癌和结肠癌的实体瘤发展中起作用，我们推测Notch活性也可能调节胃癌细胞增殖。该项目将确定Notch活性如何调节胃窦干细胞，以及胃泌素缺乏小鼠模型中的胃癌干细胞，该模型会产生自发性胃窦肿瘤。