Transcriptional Regulation of Myogenic Stem Cells

描述(申请人提供)：躯体干细胞群体存在于成人组织中，并参与成人组织的维持和再生。管理体细胞干细胞群体的信号网络定义不清。我们之前已经定义了叉头/有翼螺旋转录因子Foxk1，作为存在于成人骨骼肌中的肌肉干细胞群体的第一个分子标记。使用基因破坏策略，缺乏Foxk1的小鼠肌肉再生受损，扰乱细胞周期动力学的肌肉干细胞数量减少，并诱导了细胞周期蛋白依赖性激酶抑制剂p21的诱导。我们提供了新的初步数据，支持一种新的途径，通过Foxk1参与抑制p21的抑制复合体，从而导致肌肉干细胞群体的激活和增殖。这些初步数据为修订后的赠款申请中概述的研究提供了一个平台。这一建议的总体假设是，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特定目标：特定目标#1：确定细胞周期蛋白依赖性激酶抑制物p21CIP在肌肉干细胞群体中的转录调控。具体目标#2：确定Foxk1作为肌肉干细胞种群的关键调节因子的转录作用。特定目的#3：确定Foxk1在成人骨骼肌过表达的功能作用。这些研究将加强我们对肌源性干细胞群体的转录调控的理解，以及在一定程度上控制损伤或疾病后肌肉再生的机制。此外，这些研究的结果将作为针对获得性肌病治疗的治疗策略的平台。公共卫生相关性：先天性和获得性肌病是常见和致命的。成体组织在应对疾病或损伤时的再生能力是由常驻干细胞群体所致。目前尚不清楚肌肉干细胞的调控机制。这项提议将破译支配肌肉干细胞的分子途径，并最终可能导致针对肌病患者增强再生反应的新疗法。

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. PUBLIC HEALTH RELEVANCE: Congenital and acquired myopathies are common and deadly. The capacity of adult tissues to regenerate in response to disease or injury is due to resident stem cell populations. The regulatory mechanisms that govern muscle stem cells are unknown. This proposal will decipher the molecular pathways that govern muscle stem cells and may ultimately lead to novel therapies directed towards an enhanced regenerative response in patients with myopathic diseases.