Niche Regulation of Muscle Stem Cells

肌肉干细胞的生态位调节

• 批准号: 9979768
• 负责人: Andrew S Brack
• 金额: $ 51.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979768
• 关键词: Adult; Aging; Biomass; Cell Cycle; Cell Therapy; Cell physiology; Cells; Cellular Metabolic Process; Competence; Cytoskeleton; Data; Daughter; Degenerative Disorder; Environment; Event; Feedback; Fiber; Future; Generations; Geometry; Goals; Growth; Homeostasis; Human; Impairment; Injury; Intervention; Ligands; Molecular; Mus; Muscle; Muscle Fibers; Muscle satellite cell; Natural regeneration; Nature; Organism; PTK2 gene; Pathway interactions; Pharmacology; Phenotype; Play; Process; Proliferating; Regulation; Repression; Role; Series; Signal Transduction; Source; Testing; Time; Tissues; WNT Signaling Pathway; adult stem cell; aged; base; cell motility; gain of function; genetic approach; insight; interest; mechanotransduction; migration; muscle aging; muscle regeneration; novel; paracrine; preservation; prevent; progenitor; regenerative; response to injury; rho; satellite cell; stem cell biology; stem cells

PROJECT SUMMARY The niche is a critical regulator of long-term stem cell function. Our long-term goal is to understand the role the niche plays in regulation of muscle stem cell function. SCs reside in a quiescent state and undergo a series of transitions as they activate and proliferate. We have identified Wnt4 as a tissue resident inhibitory factor that represses activation and migration of quiescent satellite cells (QSCs) via Rho-FAK signaling. This is the first demonstration of a single paracrine acting niche factor coordinates the growth, migration and activation of QSCs. The overall goal of this proposed study is therefore to understand how Wnt4-Rho-FAK signaling axis represses activation and migration in QSCs and its implications for SC function in adult and aged mice. The first aim will combine temporal regulated and cell specific genetic strategies to modulate Wnt4 levels in muscle fibers to determine the role of Wnt4 (in muscle fibers) and Rho-FAK (in QSCs) on activation and migration in QSCs and the response to injury. The second aim will dissect the molecular mechanism that prevents QSC activation and migration via Wnt4. We will examine the role of Wnt4-Rho signaling in the repression of mTORC1 and Hippo signaling in QSCs. Understanding the role of the niche on SC function will lead to important insights for cell therapy, muscle degenerative diseases and aging.

项目概要 生态位是长期干细胞功能的关键调节因子。我们的长期目标是了解 生态位在肌肉干细胞功能的调节中发挥作用。 SC 处于静止状态并经历一系列 当它们激活和增殖时发生转变。我们已经确定 Wnt4 是一种组织驻留抑制因子 通过 Rho-FAK 信号传导抑制静止卫星细胞 (QSC) 的激活和迁移。这是第一个 证明单个旁分泌作用的生态位因子可协调生长、迁移和激活 QSC。因此，这项研究的总体目标是了解 Wnt4-Rho-FAK 信号轴如何 抑制 QSC 的激活和迁移及其对成年和老年小鼠 SC 功能的影响。第一个 目标将结合时间调节和细胞特异性遗传策略来调节肌纤维中的 Wnt4 水平 确定 Wnt4（在肌纤维中）和 Rho-FAK（在 QSC 中）对 QSC 激活和迁移的作用 以及对伤害的反应。第二个目标将剖析阻止 QSC 激活的分子机制 并通过 Wnt4 进行迁移。我们将研究 Wnt4-Rho 信号在 mTORC1 抑制中的作用， QSC 中的 Hippo 信号传导。了解利基对供应链功能的作用将为以下领域带来重要的见解： 细胞疗法、肌肉退行性疾病和衰老。