Regulation of Stem Cell Self-renewal and Differentiation

描述(申请人提供)：调节干细胞自我更新和分化的分子机制对胚胎发育和长期组织维护和修复至关重要。了解这些机制将是利用成人干细胞用于再生医学的潜力的关键。我们建议确定调控成体干细胞自我更新、维持和不对称分裂的分子机制，以在一生中维持组织动态平衡。以果蝇雄性生殖系为模型系统，我们发现支持细胞提供了调节干细胞自我更新和分化的关键微环境，干细胞朝向这个小生境建立了一个刻板的有丝分裂纺锤体，确保了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，以响应来自利基的线索。我们将阐明干细胞定向到小生境的细胞机制，以明确不对称分裂，并研究胰岛素受体信号组件如何影响干细胞行为。为了阐明决定干细胞在生态位信号下游命运的转录调控网络，我们将研究BTB结构域-锌指蛋白(S)的调控和作用模式，鉴定和研究干细胞中激活的STAT靶标的功能，并将调控干细胞行为的基因置于已知干细胞调控途径的背景下。为了研究表观遗传沉默在调控干细胞行为中的潜在保守作用，我们将测试Polycomb组转录抑制机制在干细胞或祖细胞自我更新、分裂或分化中的作用，包括PRC2组件和BMM同源物，以及染色质重塑组件。

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.