In the prior funding period, we demonstrated that conditional elimination of the Glycogen Synthase Kinase-3s (GSK-3s), a and ?, in the embryonic nervous system results in remarkable dysregulation of neural progenitor homeostasis. This result has important translational significance because of the widespread use of a GSK-3 inhibitor, lithium, in clinical practice. We hypothesize that inactivation of GSK-3s renders progenitors incapable of responding to the extracellular signals that normally regulate conversion of radial progenitors to neurons and intermediate neuronal precursors (INPs). We now propose definitive mouse genetic experiments to assess mechanisms of this GSK-3 regulation (Aims I and II). Further, we will use a chemical genetics approach to determine if reinduction of GSK-3 activity in GSK-3 deficient progenitors will result in enhanced neurogenesis (Aim III). Finally we will ask whether GSK-3 signaling regulates neural progenitors in the adult dentate gyrus (Aim IV). This work will reveal the functional potential and mechanisms of GSK-3 regulation of neural progenitors in mammals. The work will also provide information on previously unrecognized potential effects of lithium a drug commonly used in clinical practice, increasingly in children. Finally our results may suggest new ways to expand neural progenitor populations in the setting of neural transplantation.

Public Health Relevance

We propose that a specific protein, GSK-3, is a master regulator of neural stem cells. This function of GSK-3 requires investigation because a GSK-3 inhibitor, lithium, is commonly used in clinical practice, increasingly in children. Our results may also suggest new ways to expand neural stem cells in the setting of neural transplantation

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050968-09
Application #
8414160
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (02))
Program Officer
Mamounas, Laura
Project Start
2004-09-15
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
9
Fiscal Year
2013
Total Cost
$379,686
Indirect Cost
$123,141
Name
University of North Carolina Chapel Hill
Department
Neurology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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