The Mechanisms Underlying How Oxidative Stress Influences Neural Stem Cell Fate

氧化应激影响神经干细胞命运的机制

基本信息

批准号：
9513985
负责人：
Jihye Paik
金额：
$ 34.75万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9513985
关键词：
Acetylation Adult Age Aging Alzheimer&apos s Disease Antioxidants Automobile Driving Binding Brain Cell Aging Cell Culture Techniques Cell Maintenance Chromatin Cobalamin DNA DNA Methylation Data Defect Disabled Persons Elderly Epigenetic Process Equilibrium Evaluation FOXO1A gene FRAP1 gene Family Folic Acid Functional disorder Gene Expression Genes Glutamine Glutathione Homeostasis Huntington Disease Impaired cognition Impairment Injury Insulin Intervention Knowledge Learning Link Longevity Maintenance Mediating Memory Metabolic Metabolic Pathway Metabolic stress Metabolism Methionine Methylation Modification Molecular Molecular Target Natural regeneration Neurodegenerative Disorders Oligodendroglia Organ Oxidation-Reduction Oxidative Stress Parkinson Disease Pathway interactions Prevention Production Protein Isoforms Proto-Oncogene Proteins c-akt Reactive Oxygen Species Reporting Role S-Adenosylhomocysteine S-Adenosylmethionine Signal Transduction Stem cells Stress Stroke Testing Therapeutic Intervention Tissues Translating Work adult stem cell aging brain base cell growth cofactor cognitive function epigenome functional restoration histone methylation in vivo insight methylation pattern nerve stem cell neurogenesis novel strategies prevent promoter public health relevance regenerative relating to nervous system self-renewal stem stem cell fate targeted treatment transcription factor

项目摘要

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.

描述（由申请人提供）：在此提案中，我们试图了解氧化应激如何影响神经茎/祖细胞命运。越来越多的证据表明，神经干/祖细胞（NPC）的神经源性潜力降低会导致认知功能（例如学习和记忆）的缺陷，这是加速脑老化的基础。从长远来看，我们想定义功能NPC维护在老年时受到干扰的机制。转录因子的Foxo家庭是寿命的关键调节剂。我们的工作以及其他的工作表明，FOXO对于通过抑制氧化应激来维持成年干细胞池至关重要，从而将寿命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，反应性氧（ROS）的直接细胞后果被翻译为干细胞的分子老化，仍然是宽和非特异性的。这种知识差距是一个重要的问题，因为缺乏可靠的ROS分子靶标可阻止与衰老相关的NPC功能障碍的评估和预防。我们假设FOXO通过调节代谢途径和ROS的积累来抑制ROS，抑制蛋氨酸的再甲基化循环，从而导致FOXO - / - NPC的表观遗传变化和异常分化。我们将通过以下特定目的来检验我们的假设：1）表征与FOXO - / - NPC中氧化应激增加有关的代谢缺陷； 2）研究蛋氨酸合酶是NPC中ROS的靶标； 3）定义与FOXO- /-NPC中分化缺陷相关的表观遗传变化。该目标的完成将证实FOXO在NPC自我更新和分化之间的平衡中的作用，并提供了ROS的切实目标，可以利用这作为衰老大脑的干预点。这些发现还将与理解在老年扰动的干细胞维持的保守机制直接相关，并在全球范围内促进组织功能的缺陷。这些发现的应用最终可能会有所帮助延迟或扭转有害年龄的认知下降和神经退行性疾病。