Control of Stem Cell Dynamics by a Niche at Steady-State and During Aging

稳态和衰老过程中微环境对干细胞动力学的控制

• 批准号: 10159958
• 负责人: STEPHEN Francis DINARDO
• 金额: $ 41.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159958
• 关键词: Ablation; Actomyosin; Address; Aging; Architecture; Biological; Biological Assay; Biological Process; Cell physiology; Cells; Centrosome; Defect; Excision; Funding; Genetic; Genetic Transcription; Homeostasis; Image; Knowledge; Lasers; Maintenance; Mechanics; Morphogenesis; Normal Cell; Property; Regenerative Medicine; Signal Transduction; Specific qualifier value; Stress; Tissues; Work; cancer cell; cell behavior; interest; stem cells; virtual

Stem cells are necessary for tissue homeostasis, and are often localized to specialized niches that control their function. In this manner, niches control virtually all aspects of stem cell dynamics, and these properties of stem cells are essential to tissue maintenance. Recent work has shown that precise cellular architecture is important in order for a niche to communicate with fidelity to the stem cells it controls. A major issue is that the field does not understand how niches are initially formed in a tissue, nor the key cell biological steps that constitute stem cell dynamics., and how these are regulated by niche signals. Our lab made significant advances on these questions over the past five years of GM funding. First, after identifying key signals and transcriptional regulators of niche cell specification, we revealed the dynamics of niche formation by live-imaging. This enabled us to suggest mechanisms underlying niche morphogenesis that are so central to its function. We pursue the underlying mechanisms in this proposal, capitalizing on our knowledge of cytoskeletal control over cell-cell organization, and in particular the involvement of actomyosin contractility and RhoA signaling. Second, we discovered that the niche imposes precise control over fundamental cellular processes such as abscission and midbody inheritance in order to regulate stem cell dynamics during tissue homeostasis and upon stresses, such as aging. We found that dysregulations of either of these fundamental cell biological processes compromises tissue function. Furthermore, the control of midbody inheritance as detailed in the proposal should have an impact generally on our understanding of how normal and cancer cells deal with defects in centrosome number. To address our hyptheses, we combine the powerful genetic and molecalur approaches available in using Drosohila, with state-of-the-art assays in cellualr mechanics, which include high spatial and temporal live-imaging, FRAP and laser ablation. Collectively, our approaches should reveal the undelying mechnics that establish a niche properly, and reveal important cellular features that allow stem cells to maintain tissues. !

干细胞是组织稳态所必需的，通常将其定位于专门的小甲基 控制它们的功能。以这种方式，壁ches几乎可以控制干细胞动力学的所有方面， 干细胞的这些特性对于维持组织至关重要。最近的工作表明 精确的蜂窝结构对于以利基的忠诚而对茎进行交流很重要 它控制的细胞。一个主要问题是该领域不了解最初是如何形成的 组织，也不是构成干细胞动力学的关键细胞生物学步骤，它们是如何的 由利基信号监管。在过去的五个中，我们的实验室在这些问题上取得了重大进步 多年的通用汽车资金。 首先，在确定了小细胞规范的关键信号和转录调节剂后，我们揭示了 利基形成的动态通过现场模仿。这使我们能够提出基础机制 小众形态发生对其功能非常重要。我们追求这一点的基本机制 提案，利用我们对细胞细胞组织的细胞骨架控制的了解以及 特别是肌动球蛋白收缩性和RhoA信号传导的参与。 其次，我们发现利基对基本蜂窝过程施加了精确的控制 例如脱落和中体遗传，以调节组织期间的干细胞动力学 体内平衡和压力，例如衰老。我们发现其中任何一个的失调 基本细胞生物学过程损害了组织功能。此外，控制 提案中所详细介绍的中部继承应一般对我们的 了解正常和癌细胞如何处理中心体数量的缺陷。 为了解决我们的炒作，我们将可用的强大遗传和分子方法结合在一起 使用drosohila，以及最先进的指令，包括高空间和高空间和 时间现场模仿，FRAP和激光消融。 总的来说，我们的方法应该揭示出适当建立利基市场的非方便的机甲 并揭示重要的细胞特征，使干细胞保持组织。 呢