p53 Pathway in Postnatal Growth and Stem Cell Behavior

p53 产后生长和干细胞行为途径

• 批准号: 7005295
• 负责人: David A Sassoon
• 金额: $ 19.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005295
• 关键词: apoptosis; atrophy; biological signal transduction; cachexia; cell differentiation; cell growth regulation; cell proliferation; cellular oncology; developmental genetics; gene expression; genetic models; genetic regulation; genetically modified animals; laboratory mouse; muscle satellite cell; musculoskeletal regeneration; myoblasts; myogenesis; neoplasm /cancer genetics; nuclear factor kappa beta; p53 gene /protein; protein protein interaction; striated muscles; tissue /cell culture; tumor necrosis factor alpha

The processes governing stem cell generation and subsequent stem cell renewal and differentiation are poorly understood. With the exception of lower vertebrates, the existence of an identifiable and functional compartment of postnatal pluripotent stem cells which participate in multiple lineages has been difficult to identify in higher vertebrates. What limited regenerative potential mammals display declines rapidly with age and is compromised further in many disease states. We have been studying the role of PW1 which is a p53 induced gene involved in cell death and which also mediates the TNFalpha/NFkB signaling pathway. During development, PW1 is expressed during early mesodermal specification and maintained at high levels in stem cells residing in post-natal skeletal muscle. Taken together, these observations lead to the proposal that PW1 mediates stem cell behavior through p53 and cytokine/NF_B signaling pathways in these cells. We note that there is little information available regarding postnatal pluripotent stem cells due in part to their inability to undergo significant expansion in vitro and a high sensitivity to their host environment including inflammatory cytokines (i.e. TNFalpha). Related to these studies is the fact that skeletal muscle is highly sensitive to chronically elevated levels of inflammatory cytokines and undergoes wasting (cachexia) in response to TNFalpha which accounts for significant patient morbidity in cancer and chronic infection. A similar process of muscle atrophy accompanies aging and is also seen in mice with increased p53 activity. Data obtained in our laboratory has revealed an unexpected mechanistic link between the TNFalpha and p53 pathways that is unique to skeletal muscle cells which is mediated through PW1 activity. We propose these signaling pathways are active in the stem cell population and in a manner related to the ability of p53 to dictate cell fate outcomes, the p53-PW1 pathway may modulate stem cell number and competence in postnatal muscle tissue. In this proposal, we will use in vitro models (cell culture) and in vivo (mouse) models to explore the roles of PW1, p53 and cytokine signaling pathways in skeletal muscle stress responses and stem cell regulation. The relationship between the muscle stress/cachectic responses, aging and stem cell regulation is poorly understood although stem cells are required to maintain muscle growth and are thought to diminish in number and/or potential during postnatal life. We will address the central hypothesis that p53/PW1 pathways converge to regulate stem cell allocation and fate in the skeletal muscle lineage.

对干细胞产生和随后的干细胞更新和分化的过程对了解很少了解。除较低的脊椎动物外，在较高的脊椎动物中很难识别出参与多个谱系的产后多能干细胞的可识别和功能区室。有限的再生潜在哺乳动物显示出随着年龄的增长而迅速下降，并且在许多疾病状态下进一步损害。我们一直在研究PW1的作用，PW1是参与细胞死亡的p53诱导基因，还介导了TNFALPHA/NFKB信号通路。在发育过程中，PW1在中胚层规格的早期表达，并保持在产后骨骼肌中的干细胞中的高水平。综上所述，这些观察结果导致 PW1的建议通过这些细胞中的p53和细胞因子/NF_B信号通路介导干细胞行为。我们注意到，几乎没有关于产后多能干细胞的信息，部分原因是它们无法在体外进行显着扩张和对宿主环境（包括炎性细胞因子（即tnfalpha））的高敏感性。 与这些研究相关的事实是，骨骼肌对炎症性细胞因子的慢性升高水平高度敏感，并且经历了浪费（卡希克西）对TNFALPHA的响应，这构成了癌症和慢性感染的患者发病率的显着发病。伴随衰老的类似肌肉萎缩的过程，在p53增加的小鼠中也可以看到 活动。在我们的实验室中获得的数据揭示了TNFALPHA和p53途径之间的意外机械联系，这是骨骼肌细胞独有的，这是通过PW1活性介导的。我们提出这些信号通路在干细胞种群中是活跃的，并且与p53决定细胞命运结果的能力有关，p53-PW1途径可能会调节产后肌肉组织中的干细胞数量和能力。在此提案中，我们将使用体外模型（细胞培养）和体内（小鼠）模型来探索PW1，p53和细胞因子信号通路在骨骼肌应激反应和干细胞调节中的作用。肌肉应力/缓存反应之间的关系， 尽管需要干细胞来维持肌肉生长，但人们认为衰老和干细胞的调节尚不清楚，并且被认为在产后生活期间的数量和/或潜力减少。我们将解决p53/pw1途径在骨骼肌谱系中调节干细胞分配和命运的中心假设。