Somatic stem cells in the Drosophila ovary

果蝇卵巢中的成体干细胞

• 批准号: 8303025
• 负责人: DANIEL D KALDERON
• 金额: $ 32.86万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303025
• 关键词: Actins; Adhesions; Adult; Affect; Behavior; Biological Assay; Biological Models; Cancer Etiology; Cancerous; Cell Adhesion; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Proliferation; Cell model; Cell physiology; Cell-Cell Adhesion; Cells; Complement; Coupled; Cyclin E; Cyst; DNA Replication Factor; DNA biosynthesis; Daughter; Development; Drosophila genome; Drosophila genus; Environment; Equilibrium; Erinaceidae; Extracellular Matrix; Future; Genetic Screening; Genotype; Growth; Individual; Induced Mutation; Investigation; Lead; Longevity; Malignant Neoplasms; Measures; Medicine; Methods; Mitochondria; Modeling; Molecular Genetics; Mutation; Nature; Oncogenic; Ovarian Follicle; Ovary; Pathway interactions; Physiological; Positioning Attribute; Proliferating; Property; Quality Control; Reagent; Regenerative Medicine; Regulation; Role; Scheme; Screening procedure; Signal Pathway; Signal Transduction; Spatial Distribution; Stem cells; Stress; Supporting Cell; System; Testing; Tissues; cell behavior; cell type; combat; egg; extracellular; genetic analysis; human stem cells; in vivo; infancy; insight; interest; mutant; public health relevance; regenerative therapy; research study; response; self-renewal; stem cell biology; stem cell niche

DESCRIPTION (provided by applicant): Stem cells self-renew and produce daughters that generally proliferate before differentiating into a variety of cell types. These properties allow a single stem cell to produce sufficient progeny to maintain adult tissues. However, stem cell proliferation must be strictly limited according to need and must occur only in an environment that allows stem cell progeny to develop appropriately. Hence, stem cells are normally supported only in restricted, appropriately positioned micro-environments, termed niches. Most stem cell niches are hard to access or define. The Drosophila ovary, in which germline and somatic stem cell progeny collaborate to produce eggs, provides an exception that also affords the critical attribute of extensive and rapid investigation using molecular genetics. Here, somatic follicle stem cells (FSCs) in Drosophila ovaries will be used to ascertain the mechanisms by which a niche regulates stem cell behavior. Many types of stem cell niche interactions are found in nature, so insights gained from FSCs will undoubtedly both complement and strengthen those derived from other model stem cells. Particularly interesting aspects of the FSC model are regulation by multiple signaling pathways, competition between stem cells for niche positions and extensive regulation of niche adhesion. FSC dynamics and the impact of specific mutations also provide an excellent model for the retention and immortalization of pre-cancerous mutations that arise in stem cells. Execution of the first genetic screen for stem cell function in vivo, coupled with extensive testing of the role of signaling pathways on FSCs has provided key reagents, methods and hypotheses concerning stem cell function. This proposal aims to determine how individual signaling pathways affect FSCs and how multiple pathways are integrated, particularly to regulate niche adhesion. A very successful genetic screen will be extended to include more of the Drosophila genome and key mutations identified will be used to understand the fundamental circuits affecting FSC biology. This includes testing specific hypotheses that quality control uses enhanced checkpoint responses to DNA replication stress and co-ordinated regulation of the cell cycle and niche retention. FSC mutations that induce ectopic FSC duplication or displacement of neighboring FSCs provide critical reagents and impetus for understanding how stem cells compete for limited niche positions. New competition assays, FSC mutants derived from screens and signaling pathway studies will be supplemented by a new selection scheme to isolate mutations conferring enhanced competition in order to decipher both principles and players. Collectively, these studies should provide a pioneering, open-ended approach to building a comprehensive framework for the regulatory circuits that control stem cell behavior. PUBLIC HEALTH RELEVANCE: Stem cells are key vehicles for future regenerative therapies and are critical cells for the earliest steps of development of many cancers, yet very little are known about how stem cells are regulated because they are very difficult to identify and manipulate in their normal physiological setting. We propose extensive molecular genetic analyses of Drosophila ovarian follicle stem cells, which can be studied in great detail in their normal environment. Our findings will uncover basic principles of stem cell regulation that are directly relevant and of critical significance to our understanding of how to harness human stem cells in medicine and how to combat cancer.

描述(申请人提供)：干细胞自我更新，并在分化为各种细胞类型之前产生子代细胞。这些特性允许单个干细胞产生足够的后代来维持成人组织。然而，干细胞的增殖必须根据需要受到严格的限制，并且只能在允许干细胞后代适当发育的环境中进行。因此，干细胞通常只有在有限的、位置适当的微环境中才能得到支持，这些微环境被称为利基环境。大多数干细胞的利基都很难进入或定义。在果蝇卵巢中，生殖系和体细胞后代合作产生卵子，这是一个例外，也提供了利用分子遗传学进行广泛和快速研究的关键属性。在这里，将使用果蝇卵巢中的体细胞毛囊干细胞(FSCS)来确定利基调节干细胞行为的机制。自然界中发现了许多类型的干细胞生态位相互作用，因此从FSCS获得的见解无疑将补充和加强来自其他模型干细胞的见解。FSC模型特别有趣的方面是多个信号通路的调节，干细胞之间对利基位置的竞争，以及对利基黏附的广泛调节。FSC的动态和特定突变的影响也为干细胞中出现的癌前突变的保留和不朽提供了一个极好的模型。在活体内进行的第一次干细胞功能遗传筛查，加上对信号通路在胚胎干细胞上的作用的广泛测试，提供了关于干细胞功能的关键试剂、方法和假说。这项建议旨在确定单个信号通路如何影响FSCs，以及多个通路如何整合，特别是调节小生境黏附。一个非常成功的基因筛查将被扩展到包括更多的果蝇基因组，所识别的关键突变将被用来理解影响FSC生物学的基本电路。这包括测试特定的假设，即质量控制使用增强的检查点反应来应对DNA复制压力，并协调调节细胞周期和利基保留。导致邻近FSC异位复制或移位的FSC突变为理解干细胞如何竞争有限的利基位置提供了关键试剂和动力。新的竞争分析、来自筛选和信号通路研究的FSC突变体将被一个新的选择方案补充，以分离导致增强竞争的突变，以便破译原理和参与者。总而言之，这些研究应该提供一种开创性的、开放式的方法，为控制干细胞行为的调控电路建立一个全面的框架。 公共卫生相关性：干细胞是未来再生疗法的关键载体，也是许多癌症发展的早期阶段的关键细胞，但人们对干细胞是如何调控的知之甚少，因为它们在正常的生理环境下很难识别和操作。我们建议对果蝇卵泡干细胞进行广泛的分子遗传学分析，这可以在它们的正常环境中进行非常详细的研究。我们的发现将揭示干细胞调控的基本原则，这些原则直接相关，对我们理解如何在医学上利用人类干细胞以及如何抗击癌症具有至关重要的意义。