Manipulating FGFR1 Signaling to Enhance Satellite Cell Function and Potentiate Muscle Regeneration

 描述（由申请人提供）：随着年龄的增长，骨骼肌功能下降，影响生活质量，增加虚弱。修复和重建肌肉的肌肉干细胞（称为卫星细胞（SC））的损伤导致肌肉再生能力下降。SC是罕见的，通常是静止的。它们分散在整个骨骼肌组织中，激活后可以分化形成新的肌纤维或自我更新以产生新的SC。一种有吸引力的长期治疗肌肉退化的方法是将SC直接移植到衰老或患病的肌肉中，希望增加SC的数量和功能，以改善肌肉再生。然而，基于细胞的疗法存在重大障碍，包括免疫排斥、供体细胞数量不足和供体细胞的全身递送方法。避免这些困难的策略是扩大和促进内源性SC功能。为了实施这一策略，我们必须首先了解调节内源性SC扩增和体内功能的信号通路。成纤维细胞生长因子受体1（FGFR1）通过受体酪氨酸激酶信号传导，通过阻断分化和促进自我更新来调节SC。来自老年小鼠的SC中受损的FGFR1信号传导以自我更新为代价促进分化，但FGFR1信号传导的短暂体外校正恢复SC自我更新。初步数据表明，诱导组成型活性FGFR 1（称为FGFR 1 *）增加了年轻肌肉中的SC数量。该系统如何改变SC命运决定以引起扩大的数量或增加内源SC数量对再生的影响尚不清楚。使用FGFR1* 小鼠，我计划确定通过FGFR1激活来扩大年轻肌肉中的SC数量是否可以增强肌肉再生（目的1）。我还将确定FGFR1信号传导中SC自主缺陷的拯救是否有可能改善老年肌肉中的SC功能（目的2）。从年轻肌肉实验中产生的结果将为老年肌肉SC中FGFR1激活的实验提供信息。拟议的实验将深入了解FGFR1信号传导增加SC数量，增强再生和拯救年龄相关的肌肉退化的能力。该提案中的实验代表了揭示FGFR1作为肌肉再生治疗靶点的潜在作用的关键一步。

 DESCRIPTION (provided by applicant): The decline in skeletal muscle function as we age impairs quality of life and increases frailty. The impairment of muscle stem cells, called satellit cells (SCs), which repair and rebuild muscle, contributes to the decline in muscle regeneration. SCs are rare and typically quiescent. They are dispersed throughout skeletal muscle tissue, and upon activation can either differentiate to form new muscle fibers or self-renew to create new SCs. An attractive long-term treatment for muscle deterioration is to transplant SCs directly into old or diseased muscle in hopes of boosting SC numbers and function to improve muscle regeneration. However, significant hurdles for cell-based therapies exist including immune rejection, insufficient numbers of donor cells and methods for systemic delivery of donor cells. A strategy to avoid these difficulties would be to expand and promote endogenous SC function. To implement this strategy we must first understand the signaling pathways that regulate endogenous SC expansion and function in vivo. Signaling through the receptor tyrosine kinase, fibroblast growth factor receptor 1 (FGFR1) regulates SCs by blocking differentiation and promoting self- renewal. Impaired FGFR1 signaling in SCs from old mice promotes differentiation at the expense of self- renewal but transient in vitro correction of FGFR1 signalin restores SC self-renewal. Preliminary data suggests that induction of a constitutively active FGFR1 (referred to as FGFR1*) increases the number of SCs in young muscle. How this system alters SC fate decisions to cause expanded numbers or what effect boosting endogenous SC numbers has on regeneration is unknown. Using FGFR1* mice, I plan to determine if expanding SC numbers in young muscle by FGFR1 activation can enhance muscle regeneration (Aim 1). I will also determine if the rescue of the SC-autonomous defect in FGFR1 signaling has the potential to improve SC function in old muscle (Aim 2). Results generated from young muscle experiments will inform experiments on FGFR1 activation in SCs of aged muscle. The proposed experiments will provide insight into the ability of FGFR1 signaling to increase SC numbers, enhance regeneration and rescue age-related muscle degeneration. The experiments in this proposal represent a critical step toward uncovering the potential role of FGFR1 as a therapeutic target for muscle regeneration.