The objective of this project is to investigate traumatic brain injury (TBI)-induced seizures. Specifically, we will use TrkB, EphrinBS and EphB3/A4 knockout mice, as well as specific BDNF and EphrinB scavengers, to study molecular mechanisms and treatment of post-TBI seizures. Despite their clinical importance, post-TBI seizures have been largely understudied. In fact, there have been fewer than 10 experimental animal stijdies of cellular mechanisms of post-TBI seizures during the last decade, which is in striking contrast with the several thousands of publications on kindling seizures. In addition to the enormous gap between the seizure and TBI research fields, the lack of studies may also be because there were limited molecular and technical approaches to tackle this serious clinical problem. We have found dramatic cytoskeleton-related synaptic alterations in seizure-prone brain regions after TBI. Our new studies have also cleariy demonstrated that BDNF and Ephrin activities are drastically upregulated in seizure-prone brain regions after TBI. The BDNF/TrkB and Ephrin/Eph pathways control actin-dependent synaptic organization. In this proposal, we will test the hypothesis that sustained recurrence of post-TBI seizures is a consequence of overactivation of BDNF/TrkB- and/or EphrinB/EphB-mediated aberrant synaptic reorganization.
Aim 1 will investigate whether activation of BDNF/TrkB and/or EphrinB/EphB is required for the development of post-TBI seizures, by means of TrkB, EphrinBS and EphB3/A4 KO mice;
Aim 2 will study the BDNF/TrkB and/or EphrinB/EphB signaling pathways leading to enhanced seizure susceptibility after TBI;
and Aim 3 will explore tTrkB-Fc or tEphrin-Fc chimeric reagents treatments of seizure susceptibility after TBI.

Public Health Relevance

Please refer to proposal page '2'for overall project relevance to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS030291-20
Application #
8517830
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
20
Fiscal Year
2013
Total Cost
$251,465
Indirect Cost
$87,109
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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