Transcriptional Regulation of Myogenic Stem Cells

肌源干细胞的转录调控

• 批准号: 8048170
• 负责人: Daniel J. Garry
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048170
• 关键词: Address; Adult; Aging; Applications Grants; Binding; Biochemical; Biological; Biological Assay; Biological Models; Cell Cycle Kinetics; Cell Cycle Progression; Clinical; Co-Immunoprecipitations; Complex; Cyclin-Dependent Kinase Inhibitor; Data; Deterioration; Disease; Emerging Technologies; Experimental Designs; Foundations; Genes; Health; Injury; Knockout Mice; Laboratories; Lead; Maintenance; Molecular; Mus; Muscle; Muscle satellite cell; Mutagenesis; Myopathy; Natural regeneration; Nuclear; Pathway interactions; Patients; Physiological; Population; Regulation; Repression; Research; Residual state; Role; Signal Transduction; Skeletal Muscle; Stem cells; Techniques; Technology; Therapeutic; Tissues; Transcription Repressor/Corepressor; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Winged Helix; casein kinase II; exhaustion; gene repression; molecular marker; mouse model; muscle regeneration; mutant; novel; novel marker; oncoprotein p21; overexpression; programs; regenerative; research study; response; response to injury; sarcopenia; satellite cell; self-renewal; stem cell population; transcription factor

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.

描述（由申请人提供）：成体干细胞群存在于成体组织中并参与成体组织的维持和再生。控制成体干细胞群的信号网络尚不明确。我们之前已将叉头/翼状螺旋转录因子 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，从而扰乱细胞周期动力学，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，支持一种新的途径，通过该途径，Foxk1 有助于抑制 p21 的抑制复合物，从而导致肌肉干细胞群的激活和增殖。这些初步数据为研究提供了一个平台，在修订后的拨款申请中概述了这一点。该提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生肌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：确定肌肉干细胞群中细胞周期蛋白依赖性激酶抑制剂 p21CIP 的转录调控。具体目标#2：确定 Foxk1 作为肌肉干细胞群关键调节因子的转录作用。具体目标#3：确定 Foxk1 过度表达在成人骨骼肌中的功能作用。这些研究将增强我们对生肌干细胞群转录调控以及损伤或疾病后控制肌肉再生的部分机制的理解。此外，这些研究的结果将作为针对获得性肌病的治疗策略的平台。公共卫生相关性：先天性和后天性肌病很常见且致命。成体组织响应疾病或损伤而再生的能力归因于常驻干细胞群。控制肌肉干细胞的调节机制尚不清楚。该提案将破译控制肌肉干细胞的分子途径，并可能最终导致针对增强肌病患者再生反应的新疗法。