Nitric Oxide (NO) mediates many processes in the nervous system, including neurotransmission, synaptic plasticity, and excitotoxic neuronal injury. The long-term goal of this research is to delineate the mechanisms by which NO influences normal cellular homeostasis and survival so as to develop strategies to prevent neuronal cell death in neurological disorders. Preliminary experiments indicate that low concentrations of NO can increase mitochondrial number in primary rat dorsal root ganglia (DRG) neurons; the mechanisms of mitochondrial biogenesis in neurons are unknown but may involve NO and peroxisome proliferator-activated receptor y coactivator-1 (PGC-1) signaling pathways. In addition, it is possible that NO mediates its neuroprotective effects, in part, through the activation of PGC-1 in neurons and the execution of the mitochondrial biogenesis program. Therefore, the specific aims of this proposal are 1) to determine the effects of NO and the cGMP/protein kinase G pathway on mitochondrial number, 2) to investigate the regulation of mitochondrial biogenesis by PGC-1 and its downstream gene products, and 3) to determine if NO-mediated neuroprotection involves PGC-1 signaling in primary rat DRG neurons and differentiated PC12 cells. Experiments will involve the quantitation of mitochondria after exposure to NO donors or pharmacological inhibitors/activators of the cGMP pathway, evaluation of NO-induced changes in the expression of key mitochondrial biogenesis proteins, and inhibition or overexpression of PGC-1 to determine its role in mitochondrial biogenesis and neuroprotection. These experiments will address fundamental questions in neurobiology while revealing mechanisms of neuronal survival that could lead to new treatments for patients with neurological disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS049863-02
Application #
6955884
Study Section
Special Emphasis Panel (ZRG1-F03A (20))
Program Officer
Owens, David F
Project Start
2004-09-01
Project End
2006-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$49,928
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cowell, Rita M; Talati, Pratik; Blake, Kathryn R et al. (2009) Identification of novel targets for PGC-1alpha and histone deacetylase inhibitors in neuroblastoma cells. Biochem Biophys Res Commun 379:578-82
Cowell, Rita M; Blake, Kathryn R; Inoue, Tatsuya et al. (2008) Regulation of PGC-1alpha and PGC-1alpha-responsive genes with forskolin-induced Schwann cell differentiation. Neurosci Lett 439:269-74
Cowell, Rita Marie; Blake, Kathryn Rose; Russell, James W (2007) Localization of the transcriptional coactivator PGC-1alpha to GABAergic neurons during maturation of the rat brain. J Comp Neurol 502:1-18