The long term goal of the research is to identify some of the molecular mechanisms underlying post-traumatic memory deficits. Memory deficits are one of the most persistent consequences of traumatic brain injury (TBI) in humans. Mild to moderate TBI can cause memory dysfunction that lasts for months to years in the absence of any physical injury to the brain. Unfortunately, no demonstrable effective therapies for human TBI are available. In order to investigate the mechanism(s) of spatial memory dysfunction following moderate TBI, the applicant proposes to use an experimental brain injury model in rats. Memory is initially stored in a transient state and later consolidated into more long-lasting forms. Recent studies show that in both vertebrates and invertebrates, expression of Ca++/cAMP-mediated genes via CREB (Ca++/cAMP response element binding protein) is involved in memory consolidation. The applicant's hypothesis is that: the observed spatial memory deficits following moderate TBI are produced by alterations in Ca++/cAMP-mediated gene expression via CREB. The applicant proposes six related Specific Aims to test this hypothesis. He will measure the activities of Ca++/calmodulin-dependent protein kinase and cAMP-dependent protein kinase following moderate brain injury and use specific inhibitors to evaluate their in vivo roles. He will investigate the activation of CREB and the CREB antagonists (cAMP early repressor protein) and use antisense techniques to assess their contributions to spatial memory dysfunction. Finally, the applicant will examine the expression of dynorphin, a gene whose expression can be regulated by Ca++/cAMP and utilize a specific antagonist for dynorphin action to measure its role on memory deficits. The results obtained from these studies may lead to development of new molecular therapies for memory deficits associated with TBI and other neurological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS035457-04S1
Application #
6505436
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Michel, Mary E
Project Start
1997-09-15
Project End
2002-02-28
Budget Start
2000-06-01
Budget End
2002-02-28
Support Year
4
Fiscal Year
2001
Total Cost
$198,970
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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