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通路的影响。该建议的重点是凹口信号通路，该途径已知可以调节几种组织中的细胞/祖细胞增殖，细胞存活/凋亡和细胞分化等细胞过程，但尚未描述为胃。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，对最近表征的胃肛门干细胞标记LGR5的分析显示，抑制Notch信号传导的小鼠表达显着降低，这表明Notch对于维持胃腹膜中的干细胞至关重要。该建议将检验以下假设：Notch信号传导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，将使用药理学和遗传工具来操纵肛门上皮细胞中的Notch途径成分。表达由谱系特异性胃启动子驱动的CRE重组酶的小鼠菌株将与Notch激活的遗传模型交叉或Notch破坏，以研究Notch信号如何调节胃上皮干细胞的存活，增殖和谱系。对胃肿瘤中缺口的分析将利用已建立的人类胃癌细胞系，以及先前由萨缪尔森实验室生成的胃缺陷小鼠模型，该模型自发地发展为胃癌。提出了两个具体的目的：（1）检验以下假说：胃鼻干细胞受Notch信号传导调节，以通过（1A）直接靶向LGR5阳性的肛门干细胞和/或（1B）通过肛门上皮细胞命运的调节来维持组织稳态。 （2）检验以下假设，即通过（2a）在缺乏胃蛋白的小鼠中对厌食的小鼠的谱系追踪（2A）通过（2A）进行谱系追踪来测试肛门肿瘤，并确定Notch在小鼠模型和人类胃癌细胞中的作用。这些研究将共同​​提供在调节胃癌的基本信号通路方面提供出色的培训经验，使其成为胃癌生物学职业的申请人。 公共卫生相关性：胃癌是全球第四大癌症，也是与癌症相关死亡率的第二大主要原因。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，因此我们假设Notch活性也可能调节胃癌细胞的增殖。该项目将确定缺陷型干细胞以及胃癌缺陷小鼠模型中胃癌干细胞的凹槽活性如何调节，从而发展出自发的鼻肿瘤。