Somatic stem cells in the Drosophila ovary

果蝇卵巢中的成体干细胞

• 批准号: 9900793
• 负责人: DANIEL D KALDERON
• 金额: $ 36.22万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900793
• 关键词: Adult; Affect; Anterior; Behavior; Cell Differentiation process; Cell Lineage; Cell Therapy; Cells; Clonal Expansion; Communities; Complement; Complex; Development; Drosophila genus; Epithelial; Epithelium; Erinaceidae; Exhibits; Future; Genetic; Genetic Models; Genotype; Heterogeneity; Image; Individual; Institutes; Intestines; Investigation; Link; Location; Maintenance; Malignant Neoplasms; Measures; Medicine; Methods; Modeling; Movement; Mutation; Organism; Outcome; Ovary; Pathway interactions; Pattern; Population; Positioning Attribute; Production; Proliferating; Public Health; Pupa; Regulation; Reserve Stem Cell; Signal Pathway; Signal Transduction; Skin; Specific qualifier value; Supporting Cell; Testing; Therapeutic; Tissues; Visualization; WNT Signaling Pathway; adult stem cell; behavior test; cell behavior; cell community; cell type; combat; daughter cell; epithelial stem cell; genetic manipulation; human stem cells; improved; individual response; insight; mutant; premalignant; regenerative; regenerative therapy; smoothened signaling pathway; stem cell biology; stem cell division; stem cell model; stem cell proliferation; stem cells

Project Summary Adult stem cells supporting different tissues can meet the dual demands of lifelong persistence and continued production of daughter cells that differentiate through a variety of strategies, which have presumably evolved to suit demand. Highly proliferative stem cells that support continuously renewing epithelia in skin and intestines are especially important targets of investigation to understand how a large replicative burden is distributed, how mutations initiate pre-cancerous amplification, and how stem cells might be used for regenerative therapies. Somatic follicle stem cells (FSCs) in the Drosophila ovary provide an exceptional opportunity to examine highly proliferative epithelial stem cell organization, dynamics and regulation in detail. This proposal builds on extensive prior use of genetic methods for lineage tracing and direct imaging of stem cells and their progeny to construct a sophisticated and much revised picture of the location, dynamics and immediate products of a community of FSCs in their niche. The arrangement of FSCs has remarkable similarities to mammalian intestinal stem cells. In both cases, a group of about sixteen stem cells is maintained by a population asymmetry mechanism where stem cell division and differentiation are not coupled. Importantly, this leads inevitably to stabilization and amplification of faster-proliferating mutant stem cell lineages. Both types of stem cell also exhibit heterogeneous behaviors along the major developmental axis but individual stem cells also can exchange positions (“dynamic heterogeneity”). FSCs in different locations directly produce two different cell types. For FSCs, genetic interrogation of signaling pathways has defined three principal, graded external signals that regulate FSC behavior. These insights will be pursued further to build an integrated picture of FSC behavior and how it is regulated by niche signals. One objective is to define how spatially graded FSC proliferation is imposed by graded JAK-STAT and Wnt pathway signaling. A second objective is to define how these same signals specify the location and alternative differentiation outcomes for individual FSCs and the community as a whole. A third objective is to understand how FSCs and associated niche cells develop prior to adulthood under the guidance of emerging patterns of external signals. The insights gained will provide information about how stem cells co-operate and compete within a community, how niche cells communicate with stem cells, a better understanding of how some cancers can initiate and how stem cell behavior might be manipulated for therapeutic benefit.

项目摘要 支持不同组织的成人干细胞可以满足终身持续性和 继续产生通过各种策略分化的子细胞， 大概是为了满足需求而进化的高度增殖的干细胞，支持持续更新 皮肤和肠中的上皮细胞是特别重要的研究目标，以了解大的 复制负担是如何分布的，突变如何启动癌前扩增，以及干细胞如何 可以用于再生疗法。果蝇卵巢中的体卵泡干细胞（FSC）提供了 一个特殊的机会，检查高度增殖上皮干细胞的组织，动力学和 规则详细。 这项建议建立在广泛使用遗传方法的谱系追踪和直接成像的基础上 来构建一个复杂的、经过大量修改的位置图， 动态和直接产品的社区FSC在其利基。家庭服务中心的安排， 与哺乳动物肠道干细胞有着惊人的相似之处。在这两种情况下，一组约16个干 细胞是通过群体不对称机制维持的，其中干细胞分裂和分化是 不耦合。重要的是，这不可避免地导致快速增殖突变体的稳定和扩增。 干细胞谱系这两种类型的干细胞也表现出异质性行为沿着主要 干细胞在发育轴上的位置可以互换，但单个干细胞也可以互换位置（“动态异质性”）。FSCS 在不同的位置直接产生两种不同的细胞类型。对于FSC，信号的遗传询问 FSC通路定义了三种主要的、分级的外部信号来调节FSC行为。 这些见解将被进一步追求，以建立一个综合的图片FSC的行为和它是如何 由生态位信号调节。一个目的是确定空间分级的FSC增殖是如何通过 分级JAK-STAT和Wnt通路信号传导。第二个目标是确定这些相同的信号 为各个FSC和社区指定位置和替代差异化结果， 整体第三个目标是了解FSCs和相关的小生境细胞在成年前是如何发育的 在外部信号的新模式的指导下。获得的见解将提供信息 关于干细胞如何在一个群体中合作和竞争，小生境细胞如何与干细胞沟通， 细胞，更好地了解一些癌症如何启动以及干细胞的行为可能是如何发生的。 为了治疗效果而操纵。