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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Wise, Bradley C
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Santo, Evan E; Paik, Jihye (2018) A splice junction-targeted CRISPR approach (spJCRISPR) reveals human FOXO3B to be a protein-coding gene. Gene 673:95-101
Hwang, Inah; Cao, Dongqing; Na, Yoonmi et al. (2018) Far Upstream Element-Binding Protein 1 Regulates LSD1 Alternative Splicing to Promote Terminal Differentiation of Neural Progenitors. Stem Cell Reports 10:1208-1221
Santo, Evan E; Paik, Jihye (2018) FOXO in Neural Cells and Diseases of the Nervous System. Curr Top Dev Biol 127:105-118
Schäffner, Iris; Minakaki, Georgia; Khan, M Amir et al. (2018) FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis. Neuron 99:1188-1203.e6
Al-Tamari, Hamza M; Dabral, Swati; Schmall, Anja et al. (2018) FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis. EMBO Mol Med 10:276-293
Hwang, Inah; Oh, Hwanhee; Santo, Evan et al. (2018) FOXO protects against age-progressive axonal degeneration. Aging Cell 17:
Doan, Khanh V; Kinyua, Ann W; Yang, Dong Joo et al. (2016) FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase. Nat Commun 7:12733
Santo, Evan E; Paik, Jihye (2016) FOXO3a & haematopoietic stem cells: Goodbye PI3K, hello SIRT1? Cell Cycle 15:879-80
Yun, Jihye; Mullarky, Edouard; Lu, Changyuan et al. (2015) Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350:1391-6
Kim, D-Y; Hwang, I; Muller, F L et al. (2015) Functional regulation of FoxO1 in neural stem cell differentiation. Cell Death Differ 22:2034-45

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