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Somatic stem cells in the Drosophila ovary

果蝇卵巢中的成体干细胞

基本信息

批准号：
10657236
负责人：
DANIEL D KALDERON
金额：
$ 37.67万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657236
关键词：
Adult Affect Anterior Apoptosis Behavior Biological Assay Cadherins Cell Count Cell Cycle Cell Differentiation process Cell Lineage Cell Therapy Cell division Cell physiology Cells Communities Cyst Dependence Development Developmental Biology Disparate Drosophila genus Environment Epithelium Erinaceidae Event Exhibits Exposure to Extracellular Matrix Face Future Genetic Genetic Models Germ Cells Heterogeneity Human Image Individual Intestines Investigation Link Location Malignant Neoplasms Measurement Measures Mediator Medical Medicine Methods Modeling Morphology Mutation Organism Ovary Pathway interactions Pattern Phase Phosphatidylinositols Phosphotransferases Population Positioning Attribute Process Production Proliferating Property Public Health Reagent Regulation Reporter Resolution Sampling Signal Pathway Signal Transduction Skin Specific qualifier value Supporting Cell Surface System Testing Time Transcriptional Regulation Visualization WNT Signaling Pathway adult stem cell aspirate cell behavior cell community cell motility cell type combat community organizations directed differentiation environmental change extracellular fasciclin genetic analysis genetic manipulation genetic variant human stem cells insight premalignant regenerative cell regenerative therapy resilience response single-cell RNA sequencing stem cell differentiation stem cell division stem cell function stem cell model stem cell population stem cell proliferation stem cells transcriptome sequencing transmission process

项目摘要

Project Summary Adult stem cells must meet the dual demands of lifelong persistence and continued production of derivatives, as needed. Highly proliferative stem cells that support continuously renewing epithelia, as in human skin and intestines, are especially important medical targets of investigation to understand how mutations initiate pre-cancerous amplification, and how stem cells might be used for regenerative therapies. Recent investigations of Follicle Stem Cells (FSCs) in the Drosophila ovary have illuminated a detailed picture of their behavior, including direct differentiation to two different cell types, locally graded proliferation, independent regulation of division and differentiation, and remarkable similarities to the organization of mammalian intestinal stem cells. FSCs now provide an exceptional opportunity to exploit Drosophila genetics, accessibility to comprehensive high-resolution fixed and live imaging, and a relatively simple system to examine the organization, dynamics and regulation of highly proliferative adult stem cells in detail. FSCs function as a community in which individual stem cells behave stochastically and compete for niche space. FSCs directly differentiate to a quiescent cell type at the anterior face of the FSC domain and to proliferative Follicle Cells (FCs) at the posterior face. FSCs also divide more rapidly in posterior regions and dynamically exchange locations. FSC behaviors are substantially guided by the strength of two graded signaling pathways (Wnt and JAK-STAT) of opposite polarity. Potential effectors of these signals will be sought, in part, through single-cell expression profiling. Their function in regulating FSC proliferation and differentiation will be tested using established lineage analyses of genetic variants that yield quantitative measures of location, cell division and differentiation responses. These will be supplemented by new methods that examine cell cycle reporters in fixed and live samples, and by developing “GRASP” reporters of surface interactions between marked FSCs and neighboring FCs, ECM and germline cysts to explore the mechanism of FSC conversion to FCs. Adult stem cell function depends on prior development of appropriate numbers and organization of stem cells and supporting niche cells. Recent insights show that FSCs and niche cells share common precursors, with fates acquired gradually through progressive refinement of cell locations. Potential signals and mediators that guide specification of the first FCs will be investigated to provide complementary insights to those gained from studying FC formation in adults, where the morphological changes and signaling environment differ significantly. Genetic manipulations affecting division rates, differentiation and signaling profiles of the whole FSC community will be used to expose community regulative mechanisms that can modify FSC behavior, responses or the signaling environment in order to maintain stem cell numbers and function.

项目摘要成体干细胞必须满足终生持续和持续生产的双重要求衍生品，根据需要。高度增殖的干细胞，支持持续更新的上皮细胞，如在人类的皮肤和肠道是特别重要的医学调查对象，以了解如何突变启动癌前扩增，以及干细胞如何用于再生治疗。最近对果蝇卵巢中的卵泡干细胞(FSCS)的研究揭示了一个详细的他们的行为，包括直接分化为两种不同的细胞类型，局部分级增殖，独立规定的分工和分化，与组织形式显著相似哺乳动物的肠道干细胞。FSCS现在为开发果蝇提供了一个特殊的机会遗传学，可获得全面的高分辨率固定和实时成像，并且相对简单详细研究高增殖成体干细胞的组织、动力学和调控的系统。 FSCs作为个体干细胞随机行为和竞争的群落发挥作用利基空间。FSCs在FSC域的前面直接分化为静止的细胞类型，至后面部的增殖性滤泡细胞(FCS)。FSCs在后部的分裂速度也更快并动态交换位置。FSC的行为基本上是由两个等级的强度来指导的极性相反的信号通路(Wnt和JAK-STAT)。这些信号的潜在影响因素将是部分是通过单细胞表达谱来寻找的。它们在调节FSC增殖中的作用将使用已建立的遗传变异的谱系分析来测试差异，这些遗传变异产生的数量测量位置、细胞分裂和分化反应。作为补充，将有新的在固定的和活的样本中检查细胞周期报告的方法，以及通过培养“掌握”报告的方法标记的FSCS与邻近FCS、ECM和生殖系包囊之间的表面相互作用 FSC向FCS转化的机制。成体干细胞的功能依赖于先前发育的适当数量和组织干细胞和支持的利基细胞。最近的研究表明，胚胎干细胞和壁龛细胞有共同之处前体，命运是通过逐步细化细胞位置而逐渐获得的。潜在信号将对指导第一个FCS规范的调解人进行调查，以提供补充见解对于那些通过研究成人FC形成而获得的，在那里形态变化和信号环境差异显著。影响整个FSC分裂率、分化和信号特征的遗传操作社区将被用来揭露可以改变FSC行为的社区调控机制，以维持干细胞的数量和功能。