Molecular Mechanisms Regulating Drosophila Ovarian Germline Stem Cells

成体干细胞具有显著的自我更新和产生分化细胞的能力， 体内平衡。它们被证明位于生态位中并受其调节。一个主要 干细胞研究的挑战是识别和理解外在信号和内在因子的功能 控制着干细胞的自我更新这个项目的长期目标将是更好地了解 干细胞自我更新是如何由内在因素和生态位信号控制的， 生殖系干细胞（GSC）作为模型系统。果蝇卵巢是一个很有吸引力的研究系统 干细胞及其在分子和细胞水平上的生态位，由于强大的遗传学和容易识别 干细胞我们最近发现，来自生态位的Gbb/BMP 5 - 8和Dpp/BMP 2 - 4控制GSC自身， 通过抑制促分化基因BAM的表达来更新。我们还证明了E- 钙粘蛋白介导的细胞粘附是将GSC锚定到其龛位所必需的， 重塑因子ISWI和翻译调节因子Pelota是控制GSC自我更新所必需的。 然而，小生境信号如何与内在因子协同作用控制GSC的机制仍不清楚 自我更新 这项研究的三个具体目标是：（1）使用分子，遗传， 生物化学和细胞生物学方法来确定BMP信号传导如何与染色质相互作用 重塑因子以抑制BAM表达并由此维持自我更新;（2）使用以下的组合： 分子、遗传和细胞生物学方法来研究生态位活性是如何通过研究 一个新发现的小生境基因shk和BMP通路之间的遗传关系;（3）从分子和 从遗传学上表征GSC自我更新所需的基因。这项研究的结果 将导致更好地了解生态位信号和内在因素如何协同工作，以控制 GSC自我更新。控制果蝇卵巢GSC的机制可能是基础， 了解成年哺乳动物干细胞，因为来自不同生物体的干细胞具有相似的"干性" 特性.干细胞已被提倡用于治疗各种退行性疾病，如帕金森氏症和 老年痴呆症，也与癌症和衰老有关。因此，这项研究将 肯定有助于更好地了解干细胞生物学，癌症形成和衰老， 在未来的再生医学中使用干细胞

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.