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）： 人们对指导干细胞行为的电路非常感兴趣。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内在作用因子上，或识别允许其扩增同时保持其未分化状态的培养条件。因此，尽管干细胞天然生态位提供了许多控制干细胞基本特性的信号，但人们对它的了解却少之又少。了解生态位干细胞相互作用对于阐明在再生医学中使用这些细胞所需的电路至关重要。最了解的干细胞生态位系统之一是果蝇睾丸，因为干细胞及其生态位被精确定义，并且监管程序的轮廓已经到位。睾丸生态位维持生殖系干细胞和成体干细胞（分别为 GSC 和 SSC）。在这里，我们重点关注两个重要的 SSC 因子：细胞系和 zfh-1，他们的研究使我们重新考虑管理这一完善的干细胞生态位模型的规则。该提案解决了干细胞生态位生物学概念上的重要方面。首先，很少有系统能够以高分辨率研究在发育过程中区分干细胞与其利基细胞的遗传电路。目标 1A 旨在明确细胞系及其伴侣蛋白碗在介导性腺发生中 SSC 生态位命运选择中的作用。由于神经干细胞也可以产生其生态位的细胞，因此对此处确定的电路的兴趣将会很高。其次，Hedgehog 信号传导与各种干细胞类型（包括癌症干细胞）的维持有关，但 Hh 信号传导赋予干细胞的特殊特征仍然难以捉摸。目标 1B 旨在明确 Hh 在 SSC 中的作用，特别是评估干细胞的哪些定义特征是由 Hh 信号传导调节的。第三，了解抑制干细胞分化的机制是再生医学许多工作的主要目标。目标 2A 旨在确定 Zfh-1 阻止分化并赋予体细胞干细胞特性的机制。目标 2A 试图定义 Zfh-1 如何（非自主）与 GSC 中的 STAT 激活合作。 Aim 2C 提出了互补方法来识别 Zfh-1 控制下的基因，以帮助完成这两项任务。我们的工作可以从根本上为干细胞生物学的这一方面做出贡献，前景也非常好。 公共健康相关性：人们对指导干细胞行为的回路非常感兴趣。了解生态位干细胞相互作用对于阐明在再生医学中使用这些细胞所需的电路至关重要。该提案解决了干细胞生态位生物学概念上的重要方面。