Investigating the role of beta-1 integrin in regulating the adult satellite cell

描述(申请人提供)：哺乳动物的肌肉系统为运动提供机械力。这个系统在一生中都会经历重塑，并显示出从称为卫星细胞的肌肉干细胞库中再生的非凡能力。然而， 这些细胞是如何维持其静止状态和再生能力的，在很大程度上还没有确定。我建议通过使用他莫昔芬(Tmx)诱导条件等位基因b1整合素(b1整合素)的可诱导基因失活的Pax7-cre-ert2融合基因(Pax7CE等位基因)，结合谱系追踪来确定b1整合素在这些过程中的作用，以解决以下目标中概述的问题：目标1：b1整合素在静止卫星细胞中的功能：我将检查在正常稳态下b1整合素失活的卫星细胞 评估：1)静止的卫星细胞是否需要b1-整合素？2)b1-整合素的丢失是否影响 卫星细胞与细胞外基质的黏附？目的：b1-整合素在卫星细胞激活中的作用：我将利用损伤模型进一步探讨：1)b1-整合素缺失的卫星细胞是否会导致肌肉再生？2)b1-整合素缺失的卫星细胞是否会被激活并增殖？ 公共卫生相关性：小鼠的发育研究表明，b1-整合素是肌肉完整性的重要调节因子。我计划使用新开发的基因工具 明确b1整合素在正常和损伤条件下成人肌肉卫星细胞(即肌肉干细胞)中的作用。我的研究将提供对卫星细胞的细胞生物学的理解，卫星细胞具有改善肌肉营养不良的治疗潜力。

DESCRIPTION (provided by applicant): The mammalian musculature provides mechanical force for locomotion. This system undergoes remodeling throughout lifetime and displays remarkable ability to regenerate from reservoirs of muscle stem cells, called satellite cells. Yet, how these cells are maintained, both in their quiescent state as well as in their regenerative capacity, is largely undefined. I propose to define the role of b1-integrin in these processes by using a Pax7-Cre-ERT2 fusion gene (the Pax7CE allele) for tamoxifen (tmx) inducible gene inactivation of a conditional allele of b1-integrin (b1-integrinflox), coupled with lineage tracingto address the questions outlined in the aims below: Aim 1: Function of b1-integrin in the quiescent satellite cell: I will examine b1- integrin inactivated satellite cells under normal homeostasis to assess: 1) Do quiescent satellite cells require b1-integrin? 2) Does the loss of b1-integrin affect adhesion of the satellite cell to the extracellular matrix? Aim 2: Function of b1-integrin in satelite cell activation: I will use injury models to further ask: 1) Can b1-integrin null satellite cells sstain muscle regeneration? 2) Do b1- integrin null satellite cells become activated and proliferate? PUBLIC HEALTH RELEVANCE: Developmental studies in the mouse have implicated b1-integrin as an essential regulator of muscle integrity. I plan to use newly developed genetic tools to define the role of b1-integrin in adult muscle satellite cells (i.e. muscle stem cells) in norma and injured conditions. My research will provide understanding towards the cellular biology of satellite cells, which have the therapeutic potential to ameliorate muscular dystrophies.