Traumatic brain injury (TBI) is the leading cause of mortality and morbidity among young people in the Western world. Despite intensive investigative efforts, interventions designed to reduce morbidity and mortality associated with TBI [(e.g., N-methyl-D-aspartate receptor (NMDAR) antagonists)] have failed. Therefore, there is a pressing need for novel approaches for the treatment of TBI. Immediately following TBI, there is a substantial release of glutamate, leading to hyperactivation of NMDAR and excitotoxic neuronal injury. Trials of NMDAR antagonist were predicated on the notion that suppression of excitotoxicity would mitigate injury. However, recent data indicate that hyperactivation of glutamate receptors is short lived (<1 hr) and that there is a substantial reduction in NMDAR expression and signaling within 48 hr of injury. Similarly, signaling pathways and molecules that are normally associated with neuronal survival (such as BDNF, TrkR, Src, ERK, cAMP and CREB) are reduced days to weeks following TBI. These data suggest that loss of protective pro-survival signaling may be critical to neuronal injury, and restoration of protective signaling post TBI might attenuate the spread of injury and improve motor and cognitive function. Neuronal signaling can be regulated by membrane/lipid rafts (MLR), regions enriched in sphingolipids, cholesterol, and scaffolding proteins. MLR are essential for the development and stabilization of synapses and are also concentrated within neuronal growth cones. A key component of MLR is caveolin-1 (Cav-1), a cholesterol binding protein that organizes and scaffolds a multiple receptors including NMDAR, AMPAR, GPCRs, and TrkR. Hence, MLR contain the receptors and signaling molecules that are critical to neuronal survival and growth. Preliminary data from our laboratory demonstrate that 1) TBI significantly decreases MLR and their associated proteins (Cav-1, NMDAR, AMPAR, TrkR, and PSD-95);2) neuronal-targeted Cav-1 overexpression increases MLR, NMDAR, AMPAR, and TrkR;3) Cav-1 enhances BDNF-mediated phosphorylation of TrkR, Akt, and ERK1/2;4) enhances NMDAR-mediated activation of P-Src, P-CaMKII, and P-ERK1/2;5) increases NMDAR, Dopamine 1 receptor (D1R), 5-HT6, and forskolin-mediated cAMP formation;6) Cav-1 overexpression increases dendritic shaft and spine proteins (23-tubulin, neurexin1a, and drebrin) and increases dendritic sprouting and branching. Cav-1 serves as a nexus for neuronal signaling, and thus may provide a control point that can be therapeutically targeted to restore neuronal function following TBI. Accordingly, the central hypothesis of this proposal is that Cav-1 initiates MLR formation and enhances pro-survival signaling pathways, thereby promoting neuronal survival, axonal sprouting and dendritic growth that results in a substantial reduction in neuronal injury and significantly improves motor and cognitive function post TBI.

Public Health Relevance

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity among young people in the Western world. The goal of the project is to deliver a gene that will augment the brain's capacity to re-organize the neuronal circuitry following injury. As such, this project may identify a novel therapeutic approach to the treatment of TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073653-03
Application #
8575548
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2011-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$312,515
Indirect Cost
$97,040
Name
University of California San Diego
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Wang, Jiawan; Schilling, Jan M; Niesman, Ingrid R et al. (2014) Cardioprotective trafficking of caveolin to mitochondria is Gi-protein dependent. Anesthesiology 121:538-48
Head, Brian P; Patel, Hemal H; Insel, Paul A (2014) Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta 1838:532-45
Schilling, Jan M; Cui, Weihua; Godoy, Joseph C et al. (2014) Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry. Behav Brain Res 267:6-11
Niesman, Ingrid R; Zemke, Nathan; Fridolfsson, Heidi N et al. (2013) Caveolin isoform switching as a molecular, structural, and metabolic regulator of microglia. Mol Cell Neurosci 56:283-97