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 #
5R01NS039828-04
Application #
6637693
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Hicks, Ramona R
Project Start
2000-03-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2006-02-28
Support Year
4
Fiscal Year
2003
Total Cost
$253,400
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Hussain, Zubair Muhammad; Fitting, Sylvia; Watanabe, Hiroyuki et al. (2012) Lateralized response of dynorphin a peptide levels after traumatic brain injury. J Neurotrauma 29:1785-93
Anderson, Kevin J; Scheff, Stephen W; Miller, Kelly M et al. (2008) The phosphorylated axonal form of the neurofilament subunit NF-H (pNF-H) as a blood biomarker of traumatic brain injury. J Neurotrauma 25:1079-85
Guseva, Maria V; Hopkins, Deann M; Scheff, Stephen W et al. (2008) Dietary choline supplementation improves behavioral, histological, and neurochemical outcomes in a rat model of traumatic brain injury. J Neurotrauma 25:975-83
Kelso, Matthew L; Wehner, Jeanne M; Collins, Allan C et al. (2006) The pathophysiology of traumatic brain injury in alpha7 nicotinic cholinergic receptor knockout mice. Brain Res 1083:204-10
Anderson, Kevin J; Miller, Kelly M; Fugaccia, Isabella et al. (2005) Regional distribution of fluoro-jade B staining in the hippocampus following traumatic brain injury. Exp Neurol 193:125-30
Shaw, Gerry; Yang, Cui; Ellis, Rebecca et al. (2005) Hyperphosphorylated neurofilament NF-H is a serum biomarker of axonal injury. Biochem Biophys Res Commun 336:1268-77
Scheff, S W; Price, D A; Hicks, R R et al. (2005) Synaptogenesis in the hippocampal CA1 field following traumatic brain injury. J Neurotrauma 22:719-32
Gabbita, S Prasad; Scheff, Stephen W; Menard, Renee M et al. (2005) Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 22:83-94
Scheff, Stephen W; Dhillon, Harabhajan S (2004) Creatine-enhanced diet alters levels of lactate and free fatty acids after experimental brain injury. Neurochem Res 29:469-79
Pauly, J R; Charriez, C M; Guseva, M V et al. (2004) Nicotinic receptor modulation for neuroprotection and enhancement of functional recovery following brain injury or disease. Ann N Y Acad Sci 1035:316-34

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