Transcriptional Regulation of Myogenic Stem Cells

描述（由申请人提供）：体细胞干细胞群存在于成体组织中，参与成体组织的维持和再生。控制体细胞干细胞群的信号网络尚不明确。我们之前已经将叉头/翼螺旋转录因子Foxk1定义为成人骨骼肌中肌肉干细胞群的第一个分子标记。使用基因破坏策略，缺乏Foxk1的小鼠肌肉再生受损，肌肉干细胞数量减少，细胞周期动力学受到干扰，并诱导细胞周期蛋白依赖性激酶抑制剂p21。我们提供了新的初步数据，支持Foxk1参与抑制p21的新途径，从而导致肌肉干细胞群的激活和增殖。这些初步数据为本修订后的资助申请中概述的研究提供了一个平台。该建议的总体假设是谱系特异性转录调节因子相互作用并调节肌源性干细胞群以促进骨骼肌再生。为了解决这一假设，我们将追求以下三个具体目标：具体目标#1：定义细胞周期蛋白依赖性激酶抑制剂p21CIP在肌肉干细胞群体中的转录调控。具体目标#2：确定Foxk1作为肌肉干细胞群体的关键调节因子的转录作用。明确Foxk1过表达在成人骨骼肌中的功能作用。这些研究将增强我们对肌源性干细胞群体的转录调控和部分控制损伤或疾病后肌肉再生的机制的理解。此外，这些研究的结果将为治疗获得性肌病的治疗策略提供一个平台。

DESCRIPTION (provided by applicant): Somatic stem cell populations reside in adult tissues and participate in the maintenance and regeneration of adult tissues. The signaling networks that govern the somatic stem cell populations are ill defined. We have previously defined the forkhead/winged helix transcription factor, Foxk1, as the first molecular marker for the muscle stem cell population that resides in adult skeletal muscle. Using a gene disruption strategy, mice lacking Foxk1 have impaired muscle regeneration, decreased numbers of muscle stem cells that have perturbed cell cycle kinetics and an induction of the cyclin dependent kinase inhibitor, p21. We provide new preliminary data supporting a novel pathway whereby Foxk1 contributes to a repression complex that represses p21 resulting in the activation and proliferation of the muscle stem cell population. These preliminary data provide a platform for the studies, outlined in this revised grant application. The overall hypothesis of this proposal is that lineage specific transcriptional regulators interact and modulate the myogenic stem cell population to promote skeletal muscle regeneration. To address this hypothesis, we will pursue the following three specific aims: Specific Aim #1: To define the transcriptional regulation of the cyclin dependent kinase inhibitor, p21CIP in the muscle stem cell population. Specific Aim #2: To define the transcriptional role of Foxk1 as a critical regulator of the muscle stem cell population. Specific Aim #3: To define the functional role of Foxk1 overexpression in adult skeletal muscle. These studies will enhance our understanding of the transcriptional regulation of the myogenic stem cell population and the mechanisms, in part, that govern muscle regeneration following an injury or disease. Furthermore, the results of these studies will serve as a platform for therapeutic strategies directed towards the treatment of acquired myopathic diseases.