Calpains are family of calcium-activated neutral proteases involved with signal transduction and cell motility,but whose overactivation is strongly implicated in neurodegeneration following traumatic brain injury andother CMS insults and disorders. Although studies over the past 30 years have provided a wealth ofknowledge regarding calpains, important questions remain: Which calpain isoforms are responsible for theneurodegeneration? How is calpain activated postinjury? What are the critical substrates? Are m- and u-calpain located in the same subcellular compartment? We recently found that mitochondria contain u-calpain(calpain 1 plus calpain small subunit 1). Based on the existing data and our preliminary results, our workingmodel is that mitochondrial u-calpain is situated within the intermembrane space, is activated followingopening of the mitochondrial permeability transition pore (mPTP), and that mitochondrial substrates of u-calpain include apoptosis inducing factor (AIF), which when cleaved by calpain is released into the cytosoland translocates to the nucleus to contribute to caspase-independent cell death. In addition, we propose thatactivated u-calpain is released from the mitochondria into the cytosol, where its substrates are similar tothose of m-calpain. In summary, mitochondrial u-calpain is hypothesized to become activated followingmPTP opening and function as a death-related protease. We therefore hypothesize that neurons deficient incalpain 1will exhibit resistance to excitotoxic death and that neurodegeneration and functional impairmentfollowing traumatic brain injury will be markedly attenuated in mice deficient in u-calpain. Interactions withother projects include evaluating the ability of calpastatin (Project 1) and small molecule calpain inhibitors(Project 2) to inhibit mitochondrial u-calpain. This project will use the same injury models, methods ofassessing functional impairment, and methods for evaluating calpain activity as other projects, enablingdirect comparison of results. In addition, we will collaborate with the Proteomics and Biomarker Core C toidentify novel substrates of mitochondrial u-calpain. Together the experiments outlined in this project willenhance our understanding of the function of the u-calpain isoform, mechanisms involved in its activation,and its role in neuron death following traumatic brain injury and other CNS insults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS058484-01
Application #
7288121
Study Section
Special Emphasis Panel (ZNS1-SRB-R (24))
Project Start
2007-01-01
Project End
2012-12-31
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
1
Fiscal Year
2007
Total Cost
$185,483
Indirect Cost
Name
University of Kentucky
Department
Type
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
Kulbe, Jacqueline R; Geddes, James W (2016) Current status of fluid biomarkers in mild traumatic brain injury. Exp Neurol 275 Pt 3:334-352
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
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

Showing the most recent 10 out of 33 publications