The overall goal of this PPG is to evaluate the hypothesis that calpain inhibition represents a viable therapeutic target for intervention following traumatic brain injury (TBI). TBI represents a leading cause of death and disability in adults and children, and improved treatment options are urgently needed. Calpains are excessively activated following TBI and are strongly implicated in the secondary neuronal degeneration. The resultant hypothesis is that calpain inhibition will protect against the pathological and functional consequences of TBI. Although straightforward, this hypothesis has proven to be surprisingly difficult to evaluate. A handful of studies in animal models of TBI have demonstrated improved neurological recovery and attenuated axonal injury with calpain inhibitor treatment. However, evidence that these benefits are directly related to calpain inhibition has been elusive. Moreover, there are numerous unanswered questions regarding the mechanisms by which calpains contribute to cell death and dysfunction. This PPG brings together investigators with strong expertise in calpain biochemistry and in animal models of TBI to evaluate three distinct mechanisms of calpain inhibition following TBI. Project 1 explores the role of the endogenous, specific, and potent calpain inhibitor, calpastatin, in modulating calpain function and improving outcome following TBI. Project 2 is translational and will investigate the ability of new small molecule calpain inhibitors to attenuate the pathological and functional consequences of TBI. Project 3 will examine the roles of individual calpain isoforms in neurodegeneration and TBI, focusing on the hypothesis that u-calpain is a pathologic isoform and is localized to mitochondria. In addition to the three projects, there will be three cores: A, Administrative and Biostatistical Core;B, Animal Core;and C, Proteomics and Biomarker Core. Together, these projects and cores will provide a clear indication as to whether calpain inhibition represents a viable therapeutic target for TBI, and whether the small molecule calpain inhibitors are suitable for subsequent preclinical and clinical investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS058484-04
Application #
7809533
Study Section
Special Emphasis Panel (ZNS1-SRB-R (24))
Program Officer
Hicks, Ramona R
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$945,560
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Kulbe, Jacqueline R; Hall, Edward D (2017) Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology. Prog Neurobiol 158:15-44
Pleiss, Melanie M; Sompol, Pradoldej; Kraner, Susan D et al. (2016) Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function. Biochim Biophys Acta 1862:1521-32
Kulbe, Jacqueline R; Geddes, James W (2016) Current status of fluid biomarkers in mild traumatic brain injury. Exp Neurol 275 Pt 3:334-352
Hall, Edward D; Wang, Juan A; Bosken, Jeffrey M et al. (2016) Lipid peroxidation in brain or spinal cord mitochondria after injury. J Bioenerg Biomembr 48:169-74
Bolton, Amanda N; Saatman, Kathryn E (2014) Regional neurodegeneration and gliosis are amplified by mild traumatic brain injury repeated at 24-hour intervals. J Neuropathol Exp Neurol 73:933-47
Singh, Ranjana; Brewer, M Kathryn; Mashburn, Charles B et al. (2014) Calpain 5 is highly expressed in the central nervous system (CNS), carries dual nuclear localization signals, and is associated with nuclear promyelocytic leukemia protein bodies. J Biol Chem 289:19383-94
Clinkinbeard, Tiffanie; Ghoshal, Sarbani; Craddock, Susan et al. (2013) Calpain cleaves methionine aminopeptidase-2 in a rat model of ischemia/reperfusion. Brain Res 1499:129-35
Singh, Indrapal N; Gilmer, Lesley K; Miller, Darren M et al. (2013) Phenelzine mitochondrial functional preservation and neuroprotection after traumatic brain injury related to scavenging of the lipid peroxidation-derived aldehyde 4-hydroxy-2-nonenal. J Cereb Blood Flow Metab 33:593-9
Bains, Mona; Cebak, John E; Gilmer, Lesley K et al. (2013) Pharmacological analysis of the cortical neuronal cytoskeletal protective efficacy of the calpain inhibitor SNJ-1945 in a mouse traumatic brain injury model. J Neurochem 125:125-32
Ma, Marek; Ferguson, Toby A; Schoch, Kathleen M et al. (2013) Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration. Neurobiol Dis 56:34-46

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