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.
Adult brain maintains the ability to regenerate in the face of advancing age and injury by the action of neural stem cells and it is hampered by oxidative stress. We will investigate the cause and consequences of oxidative stress in neural stem cells of an aging brain. Uncovering molecular mechanism should provide novel approaches for reactivating neurogenesis to treat the degenerative brain conditions such as stroke, Alzheimer's, Parkinson's, and Huntington's.
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