Somatic stem cells in the Drosophila ovary

果蝇卵巢中的成体干细胞

• 批准号: 9220828
• 负责人: DANIEL D KALDERON
• 金额: $ 35.2万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2018-07-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220828
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adhesions; Anterior; B-Lymphocytes; Cell Adhesion; Cell Count; Cell Lineage; Cell Maintenance; Cell Proliferation; Cell model; Cells; Clone Cells; Complex; Daughter; Development; Drosophila genus; Environment; Epithelial; Erinaceidae; Future; Gap Junctions; Genetic; Genetic Models; Genetic Transcription; Genotype; Image; Imagery; Individual; Integrins; Intestines; Knowledge; Link; Literature; Location; Malignant Neoplasms; Measures; Mediating; Medicine; Methods; Modeling; Molecular; Mutation; Organism; Outcome; Ovary; Paneth Cells; Pathway interactions; Physiological; Physiology; Play; Population; Positioning Attribute; Premalignant; Property; Recording of previous events; Regulation; Reserve Stem Cell; Role; Signal Pathway; Signal Transduction; Stem Cell Factor; Stem cells; Testing; Time; WNT Signaling Pathway; adult stem cell; base; cell behavior; cell motility; cell type; combat; daughter cell; design; genetic approach; human stem cells; improved; insight; migration; public health relevance; regenerative therapy; response; self-renewal; stem cell population; transcriptome sequencing

DESCRIPTION (provided by applicant): Stem cells must self-renew and produce daughters that differentiate. Consequently, stem cells are generally supported only in restricted locations that regulate proliferation and direct appropriate daughter cell fates. Somatic follicle stem cells (FSCs) in the Drosophila ovary provide an exceptional opportunity to study how the niche environment regulates stem cell behavior. Key advantages of the FSC model include advanced knowledge of regulation by multiple signaling pathways, an important role of competition between stem cells, and regulation of both niche adhesion and proliferation as key parameters of stem cell maintenance. Both the general principles discovered about FSC dynamics and regulation, as well as the impact of specific signaling pathways will provide important insights fo understanding the normal regulation of mammalian epithelial stem cells and how pre-cancerous mutations that arise in stem cells are selected and amplified. This proposal aims first to employ multiple genetic methods for lineage tracing together with a marker of cellular proliferative histories and live imaging to extend recent studies that promise a substantial advance in our understanding of FSC numbers, arrangement and dynamics. The anticipated outcomes would reveal remarkable similarities to the dynamics of mammalian intestinal stem cells. They would also explain why FSC maintenance and competition depends critically on proliferation and would show three potential fates of FSC daughters correlated with the direction of cell migration. The proliferative contribution of relevant signaling pathways will be defined and mechanistic connections will be investigated. Specific hypotheses that Wnt and JAK-STAT signaling pathways guide FSC derivative migration and fates, and that integrins may mediate some effects of JAK-STAT signaling will be tested. Finally, transcriptional responses to signaling pathways in FSCs will be measured as part of an overall objective to understand both the general principles and the molecular steps by which the niche environment regulates FSC behaviors that fit their specific physiological purpose.

描述(由申请者提供)：干细胞必须自我更新，并产生分化的后代。因此，干细胞通常只在调节增殖和指导适当的子细胞命运的有限位置得到支持。体细胞卵泡干细胞 果蝇卵巢中的胚胎干细胞(FSCs)为研究生态位环境如何调节干细胞行为提供了一个难得的机会。FSC模型的主要优势包括先进的多信号通路调控知识，干细胞之间竞争的重要作用，以及作为干细胞维持的关键参数对利基黏附和增殖的调控。关于FSC动力学和调控的一般原理以及特定信号通路的影响都将为理解哺乳动物上皮干细胞的正常调控以及如何选择和扩增干细胞中出现的癌前突变提供重要的见解。这项建议旨在首先使用多种遗传方法进行谱系追踪，并结合细胞增殖历史和实时成像的标记，以扩展最近的研究，这些研究有望在我们对FSC的数量、排列和动态的理解方面取得实质性进展。预期的结果将揭示出与哺乳动物肠道干细胞的动力学惊人的相似之处。他们还将解释为什么FSC的维持和竞争严重依赖于增殖，并将显示FSC子代的三个潜在命运与细胞迁移的方向相关。相关信号通路的增殖作用将被定义，机制连接将被调查。Wnt和JAK-STAT信号通路指导FSC衍生品迁移和命运，以及整合素可能介导JAK-STAT信号的一些影响的具体假设将得到测试。最后，作为整体目标的一部分，我们将测量FSC对信号通路的转录反应，以了解生态位环境调节FSC行为的一般原理和分子步骤，以适应其特定的生理目的。