Traumatic brain injury (TBI) or traumatic neuronal injury (TNT) in vitro causes neuronal apoptosis, in part, through activation of caspase-3-like proteases. inhibition of caspase-3 in vitro reduces posttraumatic cell death and provides additive neuroprotection to that produced by agents that inhibit necrotic cell death. Caspase-3 activation is modulated by upstream caspases, including caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway). Our preliminary data suggests that the caspase-9 pathway appears to be more important in neurotrauma. Akt (protein kinase B) is a well-established anti-apoptotic factor, which may act, in part, by modulating caspase activation. Akt itself can also be modulated by several factors, including the novel tumor suppression protein PTEN. Recent experiments in our laboratory have suggested a role for PTEN in neuronal apoptosis. We propose to examine the role of Akt in neuronal apoptosis after TB! and TNT, and elucidate the critical upstream and downstream signal transduction pathways involved. Specific hypotheses include: 1) caspase-9, but not caspase-8, represents an important upstream modulatory mechanism for caspase-3 mediated apoptosis after trauma; 2) Akt plays an important modulatory role in apoptosis following TBI or TN! in vitro; 3) Anti-apoptotic actions of Akt include inhibition of caspase-3 activation by phosphorylating the pro-apoptotic factor BAD, as well as through other non-caspase mechanisms; 4) The recently identified tumor suppressor factor PTEN is activated after trauma or trophic withdrawal and contributes to neuronal apoptosis, in part, by downregulating Akt activity; and 5) Development of PTEN antagonists may provide a novel neuroprotective treatment strategy for CNS injury. We propose the following specific aims: 1) To examine the relative contributions of the intrinsic (caspase-9) and extrinsic (caspase-8) pathways in modulating caspase-3-induced apoptosis in TB! and TNT, using complementary in vivo and in vitro model systems; 2) To establish an anti-apoptotic role for Akt in TBI and TNT and examine proposed mechanisms, including phosphorylation of BAD. 3) To demonstrate a pro-apoptotic role for PTEN in TBI and TNI, and show that this action results substantially from its ability to downregulate Akt, resulting in activation of caspase-9 and caspase-3; and 4) To show that PTEN antagonists, newly developed by us in collaboration, are neuroprotective following injury in vivo and in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS036537-04A1
Application #
6474407
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Michel, Mary E
Project Start
1998-05-15
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
4
Fiscal Year
2002
Total Cost
$328,248
Indirect Cost
Name
Georgetown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Sabirzhanov, Boris; Stoica, Bogdan A; Hanscom, Marie et al. (2012) Over-expression of HSP70 attenuates caspase-dependent and caspase-independent pathways and inhibits neuronal apoptosis. J Neurochem 123:542-54
Faden, Alan I; Stoica, Bogdan (2007) Neuroprotection: challenges and opportunities. Arch Neurol 64:794-800
Stoica, Bogdan A; Movsesyan, Vilen A; Knoblach, Susan M et al. (2005) Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol Cell Neurosci 29:355-71
Di Giovanni, Simone; Movsesyan, Vilen; Ahmed, Farid et al. (2005) Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci U S A 102:8333-8
Movsesyan, Vilen A; Stoica, Bogdan A; Faden, Alan I (2004) MGLuR5 activation reduces beta-amyloid-induced cell death in primary neuronal cultures and attenuates translocation of cytochrome c and apoptosis-inducing factor. J Neurochem 89:1528-36
Movsesyan, V A; Stoica, B A; Yakovlev, A G et al. (2004) Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways. Cell Death Differ 11:1121-32
Yakovlev, Alexander G; Faden, Alan I (2004) Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx 1:5-16
Natale, Joanne E; Ahmed, Farid; Cernak, Ibolja et al. (2003) Gene expression profile changes are commonly modulated across models and species after traumatic brain injury. J Neurotrauma 20:907-27
Stoica, Bogdan A; Movsesyan, Vilen A; Lea 4th, Paul M et al. (2003) Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci 22:365-82
Faden, Alan I (2002) Neuroprotection and traumatic brain injury: theoretical option or realistic proposition. Curr Opin Neurol 15:707-12

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