Molecular Mechanisms Regulating Drosophila Ovarian Germline Stem Cells

描述（由申请人提供）：成体干细胞具有显著的自我更新和产生分化细胞的能力，维持成体组织的稳态。它们已被证明位于生态位中并受其调节。干细胞研究的一个主要挑战是识别和理解控制干细胞自我更新的外在信号和内在因素的功能。该项目的长期目标是利用果蝇卵巢种系干细胞（GSCs）作为模型系统，更好地了解干细胞自我更新是如何受内在因素和生态位信号控制的。果蝇卵巢由于其强大的遗传学和容易识别的干细胞，在分子和细胞水平上研究干细胞及其生态位是一个有吸引力的系统。我们最近发现，来自生态位的Gbb/BMP5-8和Dpp/BMP2-4通过抑制分化促进基因bam的表达来控制GSC的自我更新。我们还表明，E-钙粘蛋白介导的细胞粘附是将GSC固定在其生态位上所必需的，染色质重塑因子ISWI和翻译调节因子Pelota是控制GSC自我更新所必需的。然而，生态位信号如何与内在因素合作控制GSC自我更新仍不清楚。本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，确定BMP信号如何与染色质重塑因子相互作用，抑制bam表达，从而维持自我更新；(2)结合分子、遗传和细胞生物学方法，通过研究新发现的生态位基因shk与BMP通路之间的遗传关系，研究生态位活性是如何被调控的；(3)对GSC自我更新所需的基因进行分子和遗传学表征。本研究的结果将有助于更好地理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GSCs的机制可能是理解成年哺乳动物干细胞的基础，因为来自不同生物体的干细胞具有相似的“严厉”特性。干细胞一直被提倡用于治疗各种退行性疾病，如帕金森病和阿尔茨海默病，而且还与癌症和衰老有关。因此，本研究将有助于更好地理解干细胞生物学、癌症形成和衰老，以及干细胞在未来再生医学中的应用。

DESCRIPTION (provided by applicant): 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.