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，骨骼肌功能的下降会损害生活质量并增加虚弱。肌肉干细胞，即修复和重建肌肉的卫星细胞(SCs)的损伤，导致肌肉再生能力下降。SCS很少见，通常是静止的。它们分散在骨骼肌组织中，激活后既可以分化形成新的肌肉纤维，也可以自我更新产生新的干细胞。治疗肌肉退化的一种有吸引力的长期治疗方法是将干细胞直接移植到陈旧或患病的肌肉中，希望增加干细胞的数量和功能，以促进肌肉再生。然而，以细胞为基础的治疗存在重大障碍，包括免疫排斥、供体细胞数量不足以及供体细胞系统输送的方法。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体内内源性SC扩张和功能的信号通路。成纤维细胞生长因子受体1(FGFR1)通过受体酪氨酸激酶传递信号，通过阻断分化和促进自我更新来调节干细胞。老年小鼠干细胞中受损的FGFR1信号以自我更新为代价促进分化，但在体外短暂的FGFR1信号纠正可恢复SC的自我更新。初步数据表明，诱导具有结构性活性的FGFR1(称为FGFR1*)会增加年轻肌肉中的干细胞数量。这个系统如何改变SC的命运决定，从而导致数量增加，或者增加内生SC数量对再生有什么影响，目前尚不清楚。利用FGFR1*小鼠，我计划确定通过激活FGFR1来扩大年轻肌肉中的SC数量是否可以促进肌肉再生(目标1)。我还将确定挽救FGFR1信号中的SC自主缺陷是否有可能改善老年肌肉的SC功能(目标2)。年轻肌肉实验的结果将为老年肌肉干细胞中FGFR1激活的实验提供依据。拟议的实验将深入了解FGFR1信号在增加SC数量、促进再生和挽救与年龄相关的肌肉退化方面的能力。这项提案中的实验代表着朝着揭示FGFR1作为肌肉再生治疗靶点的潜在作用迈出的关键一步。

 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.