Modeling epithelial stem cell competition in a dynamic drosophila ovarian niche

项目主任/首席调查员(最后、第一、中间)：Nystul，Todd Gregory 摘要 该提案概述了一种确定允许精确指定茎的机制的策略 动态组织环境中的细胞命运和阐明干细胞竞争的机制 利基占有率。实现这项建议中的目标将是迈向长期目标的一个重要里程碑 为了发展再生医学，建立一个详细的上皮干细胞调控模型的目标-- 以治疗为基础，并了解这一过程如何在癌症等疾病状态下失败。卵泡干细胞 (FSCs)与哺乳动物上皮祖细胞有许多共同之处，很可能是一种优秀的 上皮干细胞生物学模型。像果蝇和其他几种类型的上皮干细胞一样 哺乳动物，胚胎干细胞由非专用的小生境细胞群稳定维持，并依赖于Wnt/WG 而EGFR发出自我更新的信号。此外，胚胎干细胞还会产生在整个过程中分化的子细胞。 但也保留了与常驻干细胞争夺利基市场的能力， 就像哺乳动物上皮干细胞谱系中的运输放大细胞一样。然而，准确的机制是 控制上皮干细胞生物学的这些基本特征仍然知之甚少。 基于已发表的研究和重要的初步数据，该提案的中心假设是FSC 自我更新是通过生态位内局部的自分泌和旁分泌信号建立的，而细胞 对这些小生境信号的记忆保留了新产生的子代细胞参与小生境的能力 竞争。这一假设的一个推论是，生态位竞争的遗传基础是依赖于 干细胞和潜在的替代细胞自我更新或分化的相对能力。这个 具体目标将为解决这些假设提供补充方法，包括：(1) 确定基本的生态位信号如何相互作用以精确地指定动态组织中的FSC；(2)识别 调节FSC和子代细胞命运分离的分子开关；以及(3)阐明 金融服务中心的生态位竞争机制。新开发的工具和发现WG和EGFR是特定的 金管会利基信号使实现第一个目标成为可能。第二个目标将是使用生物化学和细胞 生物学技术，并将建立在对六个家族转录因子和 格罗乔调解的镇压由文学提供。第三个目标将结合 FSC生态位功能由以前的工作和前两个目标提供，具有新的超竞争集合 突变体，以全面了解利基竞争是如何受到监管的。 这个项目意义重大，因为它将为上皮干细胞的功能提供详细的机制洞察。 细胞壁龛。这是对以往侧重于构建综合模型的研究的创新 关于FSC生态位和理解新概念、动态生态位和生机勃勃的生态位竞争。最终，它 将提供对调节上皮干细胞的保守机制的详细了解。 PHS 398/2590(11/07版)第1页续订格式页

Program Director/Principal Investigator (Last, First, Middle): Nystul, Todd Gregory Abstract This proposal outlines a strategy for identifying the mechanisms that allow for precise specification of the stem cell fate within a dynamic tissue environment and for elucidating the mechanism of competition for stem cell niche occupancy. Accomplishing the aims in this proposal will be an important milestone toward the long-term goal of building a detailed model of epithelial stem cell regulation in order to develop regenerative medicine- based therapies and understand how the process fails in disease states such as cancer. The follicle stem cells (FSCs) have many features in common with mammalian epithelial progenitors and will likely be an excellent model for epithelial stem cell biology. Like several other types of epithelial stem cells in Drosophila and mammals, FSCs are stably maintained by a non-dedicated population of niche cells and depend on Wnt/wg and EGFR signals for self-renewal. In addition, FSCs produce daughter cells that differentiate over the course of several divisions but also retain the capacity to compete with resident stem cells for niche occupancy, much like transit amplifying cells in mammalian epithelial stem cell lineages. However, the precise mechanisms that govern these fundamental features of epithelial stem cell biology remain poorly understood. Based on published studies and significant preliminary data, the central hypothesis of the proposal is that FSC self-renewal is established by localized autocrine and juxtacrine signaling within the niche, and that a cellular memory of these niche signals preserves the ability of newly produced daughter cells to participate in niche competition. A corollary to this hypothesis is the idea that the genetic basis for niche competition is dependent on the relative capacity of a stem cell and a potential replacement cell for self-renewal or differentiation. The specific aims, which will provide complementary approaches to addressing these hypotheses, are: (1) determine how essential niche signals interact to precisely specify FSCs within a dynamic tissue; (2) identify the molecular switch that regulates the segregation of FSC and daughter cell fates; and (3) elucidate the mechanism of FSC niche competition. Newly developed tools and the finding that wg and EGFR are specific FSC niche signals make it possible to achieve the first aim. The second aim will be use biochemistry and cell biology techniques, and will build from the thorough understanding of Six-family transcription factors and groucho-mediated repression provided by the literature. The third aim will combine the detailed knowledge of FSC niche function provided by previous work and the first two aims with a new collection of hypercompetition mutants to obtain a comprehensive understanding of how niche competition is regulated. This project is significant because it will provide detailed mechanistic insight into the function of epithelial stem cell niches. It is an innovative departure from previous studies that focuses on building a comprehensive model of the FSC niche and on understanding novel concepts, the dynamic niche and niche competition. Ultimately, it will provide a detailed understanding of the conserved mechanisms that regulate epithelial stem cells. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page