Molecular Mechanisms Regulating Drosophila Ovarian Germline Stem Cells

描述（由申请人提供）：成体干细胞具有自我更新和产生维持成体组织内稳态的分化细胞的显著能力。它们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子的功能。该项目的长期目标是以果蝇卵巢生殖系干细胞（GSC）为模型系统，更好地了解干细胞自我更新是如何由内在因素和小生境信号控制的。果蝇卵巢是一个有吸引力的系统，研究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的干细胞。我们最近已经表明，来自小生境的Gbb/BMP 5 -8和Dpp/BMP 2 -4通过抑制分化促进基因bam的表达来控制GSC自我更新。我们还表明，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，并且染色质重塑因子ISWI和翻译调节剂Pelota是控制GSC自我更新所必需的。然而，它仍然在很大程度上不清楚如何小生境信号与内在因素合作，以控制GSC自我更新。本研究的三个具体目标是：（1）利用分子、遗传、生物化学和细胞生物学方法的组合来确定BMP信号如何与染色质重塑因子相互作用以抑制bam表达，从而维持自我更新;（2）使用分子的组合，通过研究新发现的小生境基因shk和BMP之间的遗传关系，用遗传学和细胞生物学方法研究小生境活性是如何调节的途径;（3）对GSC自我更新所需的基因进行分子和遗传表征。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控制GSC自我更新。控制果蝇卵巢GSC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“干性”特性。干细胞已被提倡用于治疗各种退行性疾病，如帕金森病和阿尔茨海默病，并且还与癌症和衰老有关。因此，这项拟议中的研究必将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。

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.