Maintenance of calcium (Ca2+) homeostasis is extremely important not only for normal cellular function but also cell survival. The mitochondrial cycling of Ca2+ during excitotoxic insults, such as that occurring after traumatic brain injury (TBI), is key to this Ca2+ homeostasis and hence cellular homeostasis. Excessive sequestering of Ca2+ by mitochondria uncouples electron transport from ATP synthesis leading to the increased production of free radicals, and opening of the mitochondrial permeability transition pore (MPTP). The MPTP is an important component contributing to the cell death cascade. Opening of the MPTP abolishes the mitochondrial transmembrane potential (deltapsi) resulting in excessive amounts of Ca2+ and free radicals in the cytosol. Maintenance of the deltapsi is critical for synthesis of ATP, the primary energy source for the cell, which is in great demand following injury. Without an adequate source of ATP the cell has a problem maintaining Ca2+ homeostasis. The central hypothesis of this proposal is that the cycling of Ca2+ by the mitochondria is a key element in excitotoxic neuronal damage. Cyclosporin A (CsA), a widely used immunosuppressant, inhibits the opening of the MPTP and maintains mitochondrial homeostasis. We have strong evidence that systemic injections of CsA significantly reduces neuronal death in an animal model of TBI.
The specific aims of this proposal examine the following hypotheses: 1) that stabilizing mitochondrial homeostasis will stabilize cellular homeostasis and protect cortical neurons following TBI, 2) that inhibiting opening of the MPTP after TBI enhances basic metabolic functions of synapses and mitochondria, and 3) that mitochondrial homeostasis promotes synaptic plasticity following TBI. These studies will significantly enhance our understanding of the mechanisms following TBI and hopefully lead to therapies resulting in increased recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS039828-01
Application #
6084747
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Michel, Mary E
Project Start
2000-03-01
Project End
2004-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
1
Fiscal Year
2000
Total Cost
$254,042
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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