Stem Cell Renewal and Differentiation in Spermatogenesis

精子发生中的干细胞更新和分化

• 批准号: 7990313
• 负责人: STEPHEN Francis DINARDO
• 金额: $ 11.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990313
• 关键词: Accounting; Address; Adopted; Affect; Biology; Cell Communication; Cell Differentiation process; Cells; Characteristics; Cytokine Signaling; Data; Development; Drosophila genus; Ectopic Expression; Employee Strikes; Erinaceidae; Funding; Gene Targeting; Genes; Genetic; Germ Cells; Goals; Homeostasis; Maintenance; Mediating; Modeling; Molecular; Pathway interactions; Production; Property; Proteins; Recruitment Activity; Regenerative Medicine; Resolution; Role; Signal Transduction; Somatic Cell; Spermatogenesis; Stem cells; Supporting Cell; System; Testis; Tissues; Touch sensation; Undifferentiated; Work; cancer stem cell; cell behavior; cell type; daughter cell; design; expectation; interest; mutant; nerve stem cell; operation; programs; public health relevance; research study; self-renewal; smoothened signaling pathway; stem cell biology; stem cell division; stem cell niche; stem cell population

DESCRIPTION (provided by applicant): There is intense interest in the circuits that guide stem cell behavior. Due to the difficulty in identifying stem cells in tissues, most work has centered on intrinsically-acting factors that control stem cells, or on identifying culture conditions that allow their expansion while yet maintaining their undifferentiated state. Thus, there is significantly less known about the microenvironment that comprises a stem cell's natural niche, even though it provides many of the signals that govern fundamental stem cell properties. Understanding niche-stem cell interactions is central to unraveling the circuitry necessary to use these cells in regenerative medicine. One of the most well-understood stem cell-niche systems is the Drosophila testis, because the stem cells and their niche are precisely defined and the outlines of a regulatory program are in place. The testis niche maintains both germline and somatic stem cells (GSCs and SSCs, respectively). Here, two essential SSC factors, lines and zfh-1, are focused upon, and their study has led us to a reconsideration of the rules governing this well-established stem cell-niche model. This proposal addresses conceptually significant facets of stem cell-niche biology. First, there are precious few systems where one can at high resolution investigate the genetic circuitry that discriminates a stem cell from its niche cell during development. Aim 1A seeks to define the role of lines and its partner protein bowl in mediating SSC-niche fate choice in gonadogenesis. Since a neural stem cell can also generate cells of its niche, interest in the circuitry identified here will be high. Second, Hedgehog signaling has been implicated in the maintenance of various stem cell types, including cancer stem cells, but the particular characteristics that Hh signaling assigns to stem cells have remained elusive. Aim 1B seeks to define the role of Hh in SSCs, in particular, assessing which of the defining characteristics of stem cells are regulated by Hh signaling. Third, understanding the mechanisms that repress differentiation in stem cells is a major goal of much work in regenerative medicine. Aim 2A seeks to identify the mechanism whereby Zfh-1 blocks differentiation and confers stem cell properties to somatic cells. Aim 2A seeks to define how Zfh-1 cooperates (non-autonomously) with STAT activation in GSCs. Aim 2C proposes complementary approaches to identify genes under Zfh-1 control that help accomplish both of these tasks. The prospects are also excellent that our work can contribute in a fundamental manner to this aspect of stem cell biology. Public Health Relevance: There is intense interest in the circuits that guide stem cell behavior. Understanding niche-stem cell interactions is central to unraveling the circuitry necessary to use these cells in regenerative medicine. This proposal addresses conceptually significant facets of stem cell-niche biology.

描述（由申请人提供）： 对指导干细胞行为的电路充满了兴趣。由于难以识别组织中的干细胞，大多数工作都集中在控制干细胞的固有作用因素上，或者识别允许其扩展同时保持其未分化状态的培养条件。因此，尽管它提供了许多控制基本干细胞特性的信号，但对包含干细胞天然细胞的微环境的微环境鲜为人知。了解生态裂细胞的相互作用对于揭示在再生医学中使用这些细胞所需的电路至关重要。果蝇睾丸最受理解的干细胞细胞系统最受理解的是，因为精确定义了干细胞及其利基市场，并且制定了调节程序的轮廓。睾丸小裂分别保持生殖细胞和体细胞（分别为GSC和SSC）。在这里，两个基本的SSC因素，线和ZFH-1都集中在这里，他们的研究使我们重新考虑了有关这种良好的干细胞模型模型的规则。该建议在概念上涉及干细胞基因生物学的重要方面。首先，很少有在高分辨率的系统中，可以研究在发育过程中将干细胞与其生态细胞区分开的遗传回路。 AIM 1A旨在定义线条及其伴侣蛋白碗在介导SSC-Niche命运选择中的作用。由于神经干细胞也可以产生其小众细胞，因此对此处确定的电路的兴趣将很高。其次，刺猬信号传导与维持各种干细胞类型（包括癌症干细胞）有关，但是HH信号传导分配给干细胞的特定特征仍然难以捉摸。 AIM 1B试图定义HH在SSC中的作用，特别是评估干细胞的定义特征受HH信号传导调节。第三，了解抑制干细胞分化的机制是再生医学中许多工作的主要目标。 AIM 2A试图确定ZFH-1阻断分化并赋予干细胞特性到体细胞的机制。 AIM 2A试图定义ZFH-1如何与GSC中的统计激活合作（非自治）。 AIM 2C提出了互补的方法，以识别ZFH-1控制下的基因，以帮助完成这两个任务。前景也很棒，我们的工作可以以基本的方式为干细胞生物学的这一方面做出贡献。 公共卫生相关性：对指导干细胞行为的电路充满兴趣。了解生态裂细胞的相互作用对于揭示在再生医学中使用这些细胞所需的电路至关重要。该建议在概念上涉及干细胞基因生物学的重要方面。