PUBLIC STATEMENT: Traumatic brain injury (TBI) is a serious health problem suffered by 2% of the USA population with no pharmacological treatment available. This research will contribute to our understanding of how neurotrauma plays a role-in problems suffered by TBI patients by examining in mice the endoplasmic reticulum (ER) cell death pathway and how the protease caspase-12 contributes to cell death within the brain. The knowledge gleamed from this research may provide insights that could be useful in designing pharmacological treatments to alleviate the ongoing cellular loss suffered by TBI patients. The discovery that the protease caspase-12 is ER linked and activated by ER stress suggests a novel apoptotic pathway. WE HYPOTHESIZE THAT TBI INDUCES ER STRESS LEADING TO THE UNFOLDED PROTEIN RESPONSE (UPR). THIS INDUCES AND ACTIVATES PROCASPASE-12 BY CASPASE-7 AND/OR CALPAIN, WHICH CONTRIBUTES TO APOPTOTIC CELL DEATH. In the proposal's first 3 aims we will examine BiP (ER-molecular chaperone), caspase-7, caspase-12 and calpain in UPR and optimize the techniques and tools necessary to analyze their precise roles following TBI (Aims 4 &5).
SPECIFIC AIM 1 will use primary cell cultures to study BiP induction and its relationship to the activation of caspase-7, caspase-12, and calpain, and to characterize antibodies designed to specifically recognize the calpain and caspase-7 mediated caspase-12 cleavage sites.
SPECIFIC AIM 2 will examine the relative contribution of caspase-7 versus calpain in caspase-12 activation.
In SPECIFIC AIM 3 the contribution of caspase-12 to the ER apoptotic pathway in siRNA treated primary cells will be assessed.
SPECIFIC AIM 4 focuses on the relative contribution of caspase-7 versus calpain in caspase-12 activation following UPR induced by in vivo TBI using caspase-7 knockout mice. Finally, SPECIFIC AIM 5 focuses on the caspase-12 mediated ER apoptotic pathway's contribution to overall apoptotic cell death following TBI in caspase-12 knockout mice. The proposed research represents the first systematic examination of the ER apoptotic pathway after TBI. These studies will enhance our understanding of caspase-12-related cell death pathways, and provide important insights into TBI pathology that could ultimately provide therapeutic intervention and treatment of TBI related cell death, functional deficites, and linked Alzheimer's disease and epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051431-03
Application #
7340498
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Hicks, Ramona R
Project Start
2007-01-15
Project End
2011-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
3
Fiscal Year
2009
Total Cost
$353,815
Indirect Cost
Name
Banyan Biomarkers, Inc.
Department
Type
DUNS #
168789274
City
Alachua
State
FL
Country
United States
Zip Code
32615
Zhang, Zhiqun; Zoltewicz, J Susie; Mondello, Stefania et al. (2014) Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products. PLoS One 9:e92698
Mondello, Stefania; Gabrielli, Andrea; Catani, Sheila et al. (2012) Increased levels of serum MAP-2 at 6-months correlate with improved outcome in survivors of severe traumatic brain injury. Brain Inj 26:1629-35
Mondello, Stefania; Jeromin, Andreas; Buki, Andras et al. (2012) Glial neuronal ratio: a novel index for differentiating injury type in patients with severe traumatic brain injury. J Neurotrauma 29:1096-104
Mondello, Stefania; Linnet, Akinyi; Buki, Andras et al. (2012) Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury. Neurosurgery 70:666-75
Czeiter, Endre; Mondello, Stefania; Kovacs, Noemi et al. (2012) Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator. J Neurotrauma 29:1770-8
Mondello, Stefania; Papa, Linda; Buki, Andras et al. (2011) Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: a case control study. Crit Care 15:R156
Martinez, Juan A; Zhang, Zhiqun; Svetlov, Stanislav I et al. (2010) Calpain and caspase processing of caspase-12 contribute to the ER stress-induced cell death pathway in differentiated PC12 cells. Apoptosis 15:1480-93
Mondello, Stefania; Robicsek, Steven A; Gabrielli, Andrea et al. (2010) ýýII-spectrin breakdown products (SBDPs): diagnosis and outcome in severe traumatic brain injury patients. J Neurotrauma 27:1203-13
Zhang, Zhiqun; Larner, Stephen F; Liu, Ming Cheng et al. (2009) Multiple alphaII-spectrin breakdown products distinguish calpain and caspase dominated necrotic and apoptotic cell death pathways. Apoptosis 14:1289-98
Zhang, Zhiqun; Kobeissy, Firas H; Ottens, Andrew K et al. (2009) Calmodulin-binding proteome in the brain. Methods Mol Biol 566:181-90

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