Notch Regulation of Stem Cell Fate in Muscle

肌肉中干细胞命运的Notch调节

• 批准号: 8500212
• 负责人: Shihuan Kuang
• 金额: $ 31.29万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500212
• 关键词: Affect; Age; Aging; Alleles; American; Animals; Apical; Cell Communication; Cell Count; Cell Culture Techniques; Cell Lineage; Cell division; Cell physiology; Cells; Characteristics; Commit; Defect; Degenerative Disorder; Development; Equilibrium; Exhibits; Fluorescence; Goals; Growth; Health; Histocompatibility Testing; Histones; Homeostasis; Human; Impairment; Injury; Knowledge; LacZ Genes; Lead; Maintenance; Molecular; Muscle; Muscle satellite cell; Myoblasts; Myopathy; Natural regeneration; Notch Signaling Pathway; Play; Population; Population Heterogeneity; Prevention; Process; Proliferating; Regulation; Role; Signal Transduction; Signal Transduction Pathway; Skeletal Muscle; Stem cells; System; Testing; Therapeutic; Tissues; Transgenic Mice; adult stem cell; age related; aged; daughter cell; improved; in vivo; insight; loss of function; muscle aging; muscle regeneration; mutant; notch protein; novel strategies; novel therapeutic intervention; postnatal; progenitor; public health relevance; repaired; research study; response; satellite cell; self-renewal; stem; stem cell fate; tumor

DESCRIPTION (provided by applicant): Adult stem cells are defined by their capacity to differentiate into a specific tissue type while maintaining their own population through a 'self-renewal' process. A precise balance of the cell fate choice between self-renewal and differentiation is critical for stem cell function, tissue homeostasis and prevention of tumor formation. However, the molecular mechanisms regulating this process are unclear. Satellite cells in the skeletal muscle represent one of the few systems in which stem self- renewal and differentiation can be elegantly dissected. Specifically, satellite cells can asymmetrically generate self-renewal and committed daughter cells upon apical-basal, but not planar, oriented cell divisions. Our long-term goal is to understand how signals within the muscle regulate satellite cell self-renewal and differentiation, and utilize this knowledge to enhance satellite cell function and improve the repair of diseased muscles. Here, we aim to investigate the role of 'Notch' signaling in the regulation of muscle stem cell fate. The Notch signaling will be visualized using a transgenic mouse in which Notch-activated cells exhibit green fluorescence. We will then examine whether Notch signaling regulates stem cell fate and self-renewal in undamaged and regenerating muscles, respectively. We will further genetically activate or inactivate key components of the Notch signaling pathway and ask how this perturbation shifts the balance between stem cell self-renewal and differentiation. Finally, we will investigate the molecular regulation of Notch signaling in satellite cells. These studies may lead to development of novel therapeutic approaches to improve muscle repair in the aged and diseased muscles that are characterized by loss of stem cells. PUBLIC HEALTH RELEVANCE: Understanding how the developmental fate of muscle stem cells is regulated may lead to potential therapeutic approaches to enhance stem cell function and restore degenerated muscles caused by aging and muscle diseases, conditions that affect a quarter of Americans.

描述（由申请人提供）：成体干细胞的定义是其分化成特定组织类型的能力，同时通过“自我更新”过程保持自身的种群。在自我更新和分化之间的细胞命运选择的精确平衡对于干细胞功能，组织稳态和预防肿瘤形成至关重要。然而，调控这一过程的分子机制尚不清楚。骨骼肌中的卫星细胞是为数不多的系统之一，在这些系统中，干细胞的自我更新和分化可以被很好地解剖。具体来说，卫星细胞可以不对称地产生自我更新和承诺的子细胞在顶基，而不是平面，定向细胞分裂。我们的长期目标是了解肌肉内的信号如何调节卫星细胞的自我更新和分化，并利用这些知识来增强卫星细胞的功能，改善患病肌肉的修复。在这里，我们的目的是研究Notch信号在肌肉干细胞命运调节中的作用。Notch信号将在转基因小鼠中可视化，其中Notch激活的细胞显示绿色荧光。然后，我们将分别研究Notch信号是否调节未受损和再生肌肉中的干细胞命运和自我更新。我们将进一步通过基因激活或灭活Notch信号通路的关键组分，并探究这种扰动如何改变干细胞自我更新和分化之间的平衡。最后，我们将研究Notch信号在卫星细胞中的分子调控。这些研究可能会导致新的治疗方法的发展，以改善以干细胞损失为特征的衰老和病变肌肉的肌肉修复。