Molecular mechanisms of notch signaling in maintenance of melanocyte stem cells

Notch信号传导维持黑素细胞干细胞的分子机制

• 批准号: 7896583
• 负责人: Masatake Osawa
• 金额: $ 33.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896583
• 关键词: Ablation; Acceleration; Address; Age; Aging; Antioxidants; Apoptotic; Biological Models; Cell Death; Cell Survival; Color; Data; Ensure; Free Radicals; Functional disorder; Gray unit of radiation dose; Hair; Hair follicle structure; Human; Knockout Mice; Link; Maintenance; Mediating; Metabolism; Mitochondria; Molecular; Mus; Notch Signaling Pathway; Oxidative Stress; Oxidative Stress Induction; Phenotype; Physiological; Pigmentation physiologic function; Play; Population; Regenerative Medicine; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; Stress; Testing; base; cancer therapy; clinical application; inhibitor/antagonist; insight; knockout gene; melanoblast; melanocyte; mitogen-activated protein kinase p38; notch protein; novel; postnatal; premature; public health relevance; regenerative; theories; tissue regeneration

DESCRIPTION (provided by applicant): Accumulating evidence demonstrates implication of Notch signaling in the maintenance of stem cells, while the underlying molecular mechanism has remained less clear. Previously, we demonstrated the critical role of Notch signaling in the maintenance of melanocyte stem cells. Conditional ablation of Notch signaling in the melanocyte lineage results in a severe coat color dilution, followed by intensive hair graying due to apoptotic elimination of melanocyte stem cells. Although hair graying represents the most common phenotype of human aging, it remains largely unknown how aging impacts on the maintenance of melanocyte stem cells. We have found that the hair pigmentation phenotype resulting from Notch inhibition was restored by the treatment with either an antioxidant agent or an inhibitor for the stress responsible p38 MAP kinase, suggesting the implication of oxidative stress in the elimination of melanocyte stem cells. We have also identified a novel target of Notch signaling, Cidea, which was originally identified as one of pro-apoptotic factors and has been recently implicated in mitochondria metabolism. As acceleration of mitochondria metabolism is the major cause of oxidative stress, we hypothesize that Notch signaling through repressing Cidea restricts mitochondria metabolism to protect melanocyte stem cells from oxidative stress. Therefore, the focus of this application is to obtain an experimental proof of the implication of Notch signaling acting through Cidea in the regulation of oxidative stress in melanocyte stem cells. To address this hypothesis, we propose following three specific aims: Aim 1. to delineate the role of Notch signaling in protecting of melanocyte stem cells against oxidative stress; Aim 2. to clarify the role of Cidea in the regulation oxidative stress in melanocyte stem cells; and Aim 3. to elucidate the physiological link between Notch signaling and Cidea in the regulation of oxidative stress in melanocyte stem cells using the combinatory gene knockout approach in mice. Our application will uncover a novel role of Notch signaling in the maintenance of stem cells, in which Notch signaling mediates stem cell resistance to oxidative stress to ensure long-term survival of stem cells. PUBLIC HEALTH RELEVANCE. Understanding of stem cell regulation is of great importance for their clinical applications. By employing melanocyte stem cells as a model system, we will clarify a novel molecular mechanism by which stem cells are protected from oxidative stress to be ensured long-term survival.

描述（由申请人提供）：积累证据表明Notch信号在维持干细胞中的含义，而潜在的分子机制仍然不清楚。以前，我们证明了Notch信号在维持黑素细胞干细胞中的关键作用。黑素细胞谱系中Notch信号传导的条件消融会导致严重的外套颜色稀释，然后由于凋亡消除了黑色素细胞干细胞而导致的大量头发呈灰色。尽管头发灰色代表了人类衰老的最常见表型，但在很大程度上尚不清楚衰老如何影响黑素细胞干细胞的维持。我们发现，用抗氧化剂剂或抑制剂恢复了由缺口抑制作用的脱发色素沉着表型，以造成负责的p38 MAP激酶，这表明氧化应激在消除黑素细胞干细胞中的影响。我们还确定了Notch信号传导CIDEA的新目标，该靶标最初被确定为促凋亡因素之一，最近与线粒体代谢有关。由于线粒体代谢的加速是氧化应激的主要原因，因此我们假设通过抑制CIDEA通过抑制CIDEA来限制线粒体代谢来保护黑素性干细胞免受氧化应激的影响。因此，该应用的重点是获得一个实验证明，证明了通过CIDEA作用于黑色素细胞干细胞中氧化应激的Notch信号传导的意义。为了解决这一假设，我们提出以下三个具体目的：目的1。描述Notch信号在保护黑素细胞干细胞免受氧化应激中的作用；目的2。阐明CIDEA在黑色素细胞细胞中氧化应激中的作用；目的3。使用小鼠组合性基因敲除方法来调节黑素细胞干细胞中Notch信号传导与CIDEA之间的生理联系。我们的应用将揭示Notch信号在维持干细胞中的新作用，其中Notch信号传导介导了干细胞对氧化应激的抗性，以确保干细胞的长期存活。 公共卫生相关性。对干细胞调节的了解对于其临床应用至关重要。通过采用黑素细胞干细胞作为模型系统，我们将阐明一种新型的分子机制，通过该机制保护干细胞免受氧化应激，以确保长期生存。