Many neurological deficits result from the loss of neurons through neurodegenerative disease, traumatic injury, or stroke. The adult central nervous system (CNS) demonstrates little endogenous capacity for repair and lost neurons are not replaced. However, the generation of new neurons persists in two specific brain regions. Recent progress in understanding the signals regulating the proliferation and differentiation of new neurons in these two neurogenic regions, opens the possibility to use these neural stem cells, as they are collectively called, to repopulate other non-neurogenic areas of the brain that have been injured. The major goal of this study is to repopulate the injured entorhinal cortex, a region with severe cell loss in Alzheimer's disease, with neural stem cells. To achieve this goal, post-injury changes in entorhinal cortex trophic factor expression will be evaluated and neural stem cells will be grafted into the intact or injured entorhinal cortex. To determine if trophic factor expression is a limiting component of successful stem cell neuronal differentiation, ex vivo and in vivo gene therapy will be used to augment expression. These objectives will be accomplished using a combination of molecular and protein analysis, gene therapy, quantitative stereology, and modern microscopic analysis to evaluate stem cell differentiation and connectivity. By increasing our understanding of the signals required for neuronal differentiation of stem cells, this study will provide a rationale for clinical cell replacement strategies for the treatment of various neurodegenerative diseases and traumatic injuries where neuron loss is experienced.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-2 (01))
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Wise, Bradley C
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Rosalind Franklin University
Schools of Medicine
North Chicago
United States
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Bazarek, Stanley; Peterson, Daniel A (2014) Prospects for engineering neurons from local neocortical cell populations as cell-mediated therapy for neurological disorders. J Comp Neurol 522:2857-76
Schmitz, Christoph; Eastwood, Brian S; Tappan, Susan J et al. (2014) Current automated 3D cell detection methods are not a suitable replacement for manual stereologic cell counting. Front Neuroanat 8:27
Hafez, D M; Huang, J Y; Richardson, J C et al. (2012) F-spondin gene transfer improves memory performance and reduces amyloid-? levels in mice. Neuroscience 223:465-72
Klempin, Friederike; Marr, Robert A; Peterson, Daniel A (2012) Modification of pax6 and olig2 expression in adult hippocampal neurogenesis selectively induces stem cell fate and alters both neuronal and glial populations. Stem Cells 30:500-9
Bernal, Giovanna M; Peterson, Daniel A (2011) Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells. Aging Cell 10:466-82
Encinas, Juan M; Michurina, Tatyana V; Peunova, Natalia et al. (2011) Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8:566-79
Marr, Robert A; Thomas, Rosanne M; Peterson, Daniel A (2010) Insights into neurogenesis and aging: potential therapy for degenerative disease? Future Neurol 5:527-541
Lazarov, Orly; Mattson, Mark P; Peterson, Daniel A et al. (2010) When neurogenesis encounters aging and disease. Trends Neurosci 33:569-79
Thomas, Rosanne M; Hotsenpiller, Gregory; Peterson, Daniel A (2007) Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J Neurosci 27:2734-43
Thomas, Rosanne M; Urban, Janice H; Peterson, Daniel A (2006) Acute exposure to predator odor elicits a robust increase in corticosterone and a decrease in activity without altering proliferation in the adult rat hippocampus. Exp Neurol 201:308-15

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