Regulation of Stem Cell Self-renewal and Differentiation

描述（由申请人提供）：调节干细胞自我更新和分化的分子机制对于胚胎发育和长期组织维持和修复至关重要。了解这些机制将是利用成体干细胞用于再生医学的潜力的关键。我们建议确定调节成体干细胞自我更新、维持和不对称分裂以维持整个生命期组织稳态的分子机制。使用果蝇雄性生殖系作为模型系统，我们发现，支持细胞提供了一个至关重要的微环境，调节干细胞自我更新和分化，干细胞朝向这个小生境建立一个定型的有丝分裂纺锤体，确保干细胞分裂的正常不对称结果。我们现在建议利用我们已经建立的强大的系统和工具来识别调节干细胞行为的分子电路，以响应来自小生境的线索。我们将阐明定向干细胞的生态位，以指定不对称分裂的细胞机制，并调查胰岛素受体信号成分如何影响干细胞的行为。为了阐明转录调控网络，指定干细胞的命运下游的小生境信号，我们将调查/o/a BTB结构域锌指蛋白（S）的调节和作用模式，确定和研究激活STAT在干细胞中的目标的功能，并放置基因，调节干细胞的行为在已知的干细胞调控途径的背景下。为了研究表观遗传沉默在调节干细胞行为中的潜在保守作用，我们将测试Polycomb组转录抑制机制的作用，包括PRC 2组分和BmM同系物，以及染色质重塑组分，在干细胞或祖细胞自我更新，分裂或分化中。

DESCRIPTION (provided by applicant): The molecular mechanisms that regulate stem cell self renewal and differentiation are crucial for embryonic development and for long term tissue maintenance and repair. Understanding these mechanisms will be key for harnessing the potential of adult stem cells for regenerative medicine. We propose to identify molecular mechanisms that regulate adult stem cell self- renewal, maintenance and asymmetric division to maintain tissue homeostasis throughout life. Using the Drosophila male germ line as a model system, we discovered that support cells provide a crucial microenvironment that regulates both stem cell self renewal and differentiation, and that stem cells orient toward this niche to set up a stereotyped mitotic spindle, ensuring the normally asymmetric outcome of stem cell divisions. We now propose to utilize the powerful system and tools we have established to identify the molecular circuitry that regulates stem cell behavior in response to cues from the niche. We will elucidate the cellular mechanisms that orient stem cells to the niche to specify asymmetric division and investigate how insulin receptor signaling components affect stem behavior. To elucidate the transcriptional regulatory network that specifies stem cell fate downstream of niche signals, we will investigate the regulation and mode of action of /o/a BTB domain-Zn finger protein(s), identify and investigate the function of targets of activated STAT in stem cells, and place genes that regulate stem cell behavior in the context of known stem cell regulatory pathways. To investigate the potentially conserved role of epigenetic silencing in regulating stem cell behavior, we will test roles of Polycomb group transcriptional repression machinery, including PRC2 components and BmM homologs, as well as chromatin remodeling components, in stem or progenitor cell self-renewal, division or differentiation.