The Mechanisms Underlying How Oxidative Stress Influences Neural Stem Cell Fate

描述（由申请人提供）：在本提案中，我们试图了解氧化应激如何影响神经干/祖细胞的命运。越来越多的证据表明，神经干/祖细胞（NPCs）的神经发生潜能下降会导致学习和记忆等认知功能的缺陷，这是大脑加速衰老的基础。从长远来看，我们希望确定在老年时功能性npc的维护受到干扰的机制。foxo转录因子家族是长寿的关键调节因子。我们和其他人的研究表明，FoxO通过抑制氧化应激对维持成体干细胞库至关重要，从而将长寿与衰老组织的再生潜力联系起来。氧化应激越来越被认为是器官干细胞衰老相关功能障碍的驱动原因。然而，活性氧（ROS）的直接细胞后果被翻译为干细胞的分子老化，仍然是广泛和非特异性的。这种知识差距是一个重要问题，因为缺乏可靠的ROS分子靶标，阻碍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，而ROS的积累抑制了导致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FoxO-/- NPC中与氧化应激增加相关的代谢缺陷；2)研究蛋氨酸合成酶作为NPC中ROS脱调控的靶点；3)明确FoxO- /- NPC分化缺陷相关的表观遗传变化。这一目标的完成将证实FoxO在NPC自我更新和分化之间的平衡中的作用，并提供ROS的切实目标，可以作为大脑衰老的干预点。这些发现也将与理解干细胞维持的保守机制直接相关，这些机制在老年时受到干扰，并在全球范围内导致组织功能的获得性缺陷。这些发现的应用最终可能会有所帮助

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.