Integrin signaling in skeletal muscle regeneration

项目总结 在骨骼肌中，Pax7+卫星细胞(SCs)是一种静止的肌肉干细胞群体， 在受伤时被激活，并产生迁移、分裂和融合的祖细胞以产生新的 肌肉。我们对肌肉再生过程中的这些过程的理解是不完整的。中环 这个提议的假设是，干细胞利用整合素信号来实现特定的功能。SCS位于 肌纤维表面和周围有细胞外基质(ECM)。主要ECM绑定 细胞表面的受体是整合素异二聚体，由一个α-整合素和一个β-整合素组成。 整合素将细胞锚定在细胞外基质上，并连接到肌动蛋白细胞骨架上。与细胞外基质结合后，整合素 细胞内信号，通常与生长因子受体协同作用。SCs表达许多整合素，它们 需要对其进行系统研究，才能了解SC生物学。这项提议是一个长期的 计划探索整合素如何将自身整合到SC功能的特定方面： 目的1：梳理β1整合素在SC功能中的调节信号：我们将确定β1整合素是如何 下游效应器通过与FGF2的合作促进SC的增殖和自我更新，并有可能 使用WNT7a。 目的2：确定β3整合素在SC功能中的作用：β3整合素和β1整合素均可形成 细胞外基质成分纤维粘连蛋白，在肌肉再生中起作用。我们将测定β3-整合素 在供应链中发挥作用。 目的：为了确定ILK在体内SC功能中的作用：ILK(整合素连接的激酶)存在于基底 SCs的细胞膜为β1整合素。我们将破译ILK在SC中的角色。我们还将确定是否 以及ILK如何在SCs的整合素-FGF2协同作用中发挥作用。 。

PROJECT SUMMARY Within the skeletal muscle, Pax7+ satellite cells (SCs) are a quiescent muscle stem cell population that becomes activated upon injury and gives rise to progenitors that migrate, divide, and fuse to generate new muscles. Our understanding for these processes during muscle regeneration is incomplete. The central hypothesis of this proposal is that SCs utilize integrin signaling for specialized functions. SCs are located on the muscle fiber surface and surrounded by the extracellular matrix (ECM). The primary ECM binding receptors on the cell surface are the integrin heterodimers, composed of one a-integrin and one β-integrin. Integrins anchor cells to the ECM and tether to the actin cytoskeleton. Upon binding to the ECM, integrins signal intracellularly, frequently in concert with growth factor receptors. SCs express many integrins, and they need to be studied systematically to understand SC biology. This proposal is the beginning of a long-term plan to explore how integrins integrate themselves into specific aspects of SC function: Aim 1: To tease out β1-integrin-regulated signaling in SC function: We will determine how β1-integrin's downstream effectors enhance SC proliferation and self-renewal, via cooperation with FGF2, and potentially with Wnt7a. Aim 2: To determine the role of β3-integrin in SC function: Both β3- and β1-integrins can form receptors for the ECM component fibronectin, which has a role in muscle regeneration. We will determine β3-integrin's function in the SC. Aim3: To determine the role of ILK in SC function in vivo: ILK (integrin linked kinase) is present at the basal membrane of SCs as β1-integrin. We will decipher the role of ILK in the SC. We will also determine whether and how ILK plays a role in integrin-FGF2 synergy in SCs. .