The Mechanisms Underlying How Oxidative Stress Influences Neural Stem Cell Fate

描述(由申请人提供)：在这项建议中，我们试图了解氧化应激如何影响神经干细胞/祖细胞的命运。越来越多的证据表明，神经干/祖细胞(NPC)神经发生潜能的降低导致学习和记忆等认知功能的缺陷，这是加速大脑衰老的基础。从长远来看，我们想要定义的机制，功能的鼻祖细胞的维持在老年时受到干扰。FoxO转录因子家族是长寿的关键调节因子。我们和其他人的工作表明，FoxO通过抑制氧化应激，从而将寿命与老化组织的再生潜力联系起来，对于维持成人干细胞库至关重要。氧化应激日益被认为是器官干细胞衰老相关功能障碍的驱动因素。然而，被翻译为干细胞分子老化的活性氧物种(ROS)对细胞的直接影响仍然是广泛和非特异性的。这种认识差距是一个重要的问题，因为缺乏可靠的ROS分子靶点阻止了对衰老相关鼻咽癌功能障碍的评估和预防。我们假设FoxO通过调节代谢途径抑制ROS，ROS的积累抑制导致FoxO-/-NPC表观遗传变化和异常分化的蛋氨酸再甲基化循环。我们将通过以下具体目标来验证我们的假设：1)表征与FoxO-/-NPC氧化应激增加相关的代谢缺陷；2)研究蛋氨酸合成酶作为鼻咽癌ROS解除调控的靶标；以及3)定义与FoxO-/-NPC分化缺陷相关的表观遗传学变化。这一目标的完成将证实FoxO在鼻咽癌自我更新和分化之间的平衡中所起的作用，并为ROS提供一个有形的靶点，可以作为脑老化的干预点。这些发现还将直接与理解干细胞维持的保守机制有关，这些机制在老年时受到干扰，并在全球范围内导致获得性组织功能缺陷。这些发现的应用最终可能会有所帮助 延缓或逆转有害的年龄--进行性认知衰退和神经退行性疾病。

DESCRIPTION (provided by applicant): In this proposal we seek to understand how oxidative stress influences neural stem/progenitor cell fate. Growing evidence indicates that decreased neurogenic potential of neural stem/progenitor cells (NPCs) contributes to a deficit in cognitive functions such as learning and memory, serving as a basis for accelerated brain aging. In the long term we want to define the mechanisms by which maintenance of functional NPCs is perturbed in old age. The FoxO-family of transcription factors is a key modulator of longevity. Our work, and that of others, has demonstrated that FoxO is crucial for maintaining adult stem cell pools by suppressing oxidative stress, thereby connecting longevity with regenerative potential of aging tissues. Oxidative stress is increasingly recognized as a driving cause of aging-associated dysfunction of organ stem cells. However, direct cellular consequences of reactive oxygen species (ROS) that is translated as molecular aging of stem cells remain as broad and non-specific. Such knowledge gap is an important problem as lack of reliable molecular targets of ROS prevents evaluation and prevention of aging-associated NPC dysfunction. We hypothesize that FoxO suppresses ROS by regulating metabolic pathways and accumulation of ROS inhibits methionine re-methylation cycle that causes epigenetic changes and aberrant differentiation in FoxO-/- NPC. We will test our hypothesis by following specific aims: 1) Characterize the metabolic defects associated with increased oxidative stress in FoxO-/- NPC; 2) Investigate methionine synthase as a target of deregulated ROS in NPC; and 3) Define epigenetic changes associated with differentiation defects in FoxO- /- NPC. Completion of this aim will substantiate the role of FoxO in the balance between NPC self-renewal and differentiation and provide a tangible target of ROS that could be exploited as an intervention point for the aging brain. The findings will also have direct relevance to understanding conserved mechanisms of stem cell maintenance that are perturbed in old age and contribute globally to acquired deficits in tissue function. Application of these findings ultimately may help to delay or reverse the detrimental age- progressive cognitive decline and neurodegenerative diseases.