Molecular Mechanisms Regulating Drosophila Ovarian Germline Stem Cells

调节果蝇卵巢生殖干细胞的分子机制

• 批准号: 7333264
• 负责人: TING XIE
• 金额: $ 27.03万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333264
• 关键词: Adult; Advocate; Aging; Alzheimer' s Disease; Binding; Biochemical; Biological; Biological Models; Cell Adhesion; Cell Differentiation process; Cells; Cellular biology; Chromatin Remodeling Factor; Complex; Degenerative Disorder; Drosophila genus; E-Cadherin; Future; Genes; Genetic; Genetic Screening; Goals; Homeostasis; ISWI; In Vitro; Intrinsic factor; Lead; Malignant Neoplasms; Mediating; Molecular; Molecular Genetics; NURF; Organism; Ovarian; Ovary; Parkinson Disease; Pathway interactions; Phenotype; Property; Protein Overexpression; Recruitment Activity; Regenerative Medicine; Regulation; Research Personnel; Signal Transduction; Stem Cell Research; Stem cells; System; Tissues; Transducers; Translations; Ursidae Family; Work; adult stem cell; gene function; in vivo; novel; programs; receptor; self-renewal; tool; tumor

Adult stem cells have remarkable ability to self-renew and generate differentiated cells that maintain homeostasis in adult tissues. They have been shown to be located in and regulated by the niche. A major challenge in stem cell research is to identify and understand functions of extrinsic signals and intrinsic factors that control stem cell self-renewal. The long-term goal of this project will be to gain a greater understanding of how stem cell self-renewal is controlled by intrinsic factors and niche signals using Drosophila ovarian germline stem cells (GSCs) as a model system. The Drosophila ovary represents an attractive system to study stem cells and their niche at the molecular and cellular level due to powerful genetics and easily identified stem cells. We have recently shown that Gbb/BMP5-8 and Dpp/BMP2-4 from the niche control GSC self- renewal by repressing expression of a differentiation-promoting gene bam. We have also shown that E- cadherin-mediated cell adhesion is required for anchoring GSCs to their niche and that a chromatin remodeling factor ISWI and a translation regulator Pelota are required for controlling GSC self-renewal. However, it still remains largely unclear how niche signals cooperate with intrinsic factors to control GSC self-renewal. Three specific aims of this proposed study are:(1) to use a combination of molecular, genetic, biochemical and cell biological approaches to determine how BMP signaling interacts with chromatin remodeling factors to repress bam expression and thereby maintain self-renewal; (2) to use a combination of molecular, genetic and cell biological approaches to investigate how niche activity is regulated by studying genetic relationships between a newly identified niche gene shk and the BMP pathway; (3) to molecularly and genetically characterize genes that are required for GSC self-renewal. The results from this proposed study will lead to a greater understanding of how niche signals and intrinsic factors work cooperatively to control GSC self-renewal. The mechanisms controlling Drosophila ovarian GSCs are likely fundamental to understanding adult mammalian stem cells since stem cells from diverse organisms share similar "sternness" properties. Stem cells have been advocated to treat a variety of degenerative diseases such as Parkinson's and Alzheimer's diseases, and have also been connected to cancer and aging. Therefore, this proposed study will surely contribute to a better understanding of stem cell biology, cancer formation and aging as well as to using stem cells in future regenerative medicine.

成年干细胞具有显着的自我更新和生成维持的分化细胞的能力 成人组织中的稳态。它们已被证明位于利基市场中并监管。专业 干细胞研究中的挑战是识别和理解外部信号和内在因素的功能 控制干细胞自我更新。该项目的长期目标是获得更大的了解 干细胞自我更新如何受到固有因素和利基信号的控制 种系干细胞（GSC）作为模型系统。果蝇卵巢代表了一个有吸引力的研究系统 由于强大的遗传学，干细胞及其在分子和细胞水平的小众市场，易于鉴定 干细胞。我们最近显示，来自利基控制GSC自我的GBB/BMP5-8和DPP/BMP2-4 通过抑制促进分化基因BAM的表达来更新。我们还表明了e- 钙粘蛋白介导的细胞粘附是将GSC锚定在其利基市场上需要的，并且是染色质的 控制GSC自我更新需要重塑因子ISWI和翻译调节器Pelota。 但是，仍然尚不清楚利基信号如何与控制GSC的内在因素合作 自我更新。 这项拟议的研究的三个具体目的是：（1）结合分子，遗传， 生化和细胞生物学方法来确定BMP信号如何与染色质相互作用 重塑因素抑制BAM表达并保持自我更新； （2）结合 分子，遗传和细胞生物学方法研究如何通过研究来调节利基活性 新确定的利基基因SHK和BMP途径之间的遗传关系； （3）到分子和 遗传表征GSC自我更新所需的基因。这项拟议的研究的结果 将对利基信号和固有因素如何合作控制的更深入地了解 GSC自我更新。控制果蝇卵巢GSC的机制可能对 了解成年哺乳动物干细胞，因为来自各种生物的干细胞具有相似的“严厉” 特性。已主张干细胞治疗各种退化性疾病，例如帕金森氏症和 阿尔茨海默氏症的疾病，也与癌症和衰老有关。因此，这项拟议的研究将 肯定有助于更好地了解干细胞生物学，癌症形成和衰老以及 在未来的再生医学中使用干细胞。