Ocular and traumatic brain injuries (TBI) from blunt trauma or blast injury to the head occur with high frequency on the battlefield, and they are often accompanied by multiple visual dysfunctions, acuity loss and blindness in one or both eyes. Optic neuropathies are characterized by primary injury to the optic nerve, and loss of ganglion cells and their axons. Ganglion cell death is mediated in part by excessive intracellular Ca2+ ([Ca2+]i) loads following injury. Consistent with this finding is the enhancement of retinal ganglion cell survival after optic nerve crush with the administration of Ca2+ channel antagonists, which inhibit both L- and T-type Ca2+ currents, and reduce secondary ganglion cell death. The rationale underlying the proposed studies is that reduction of ganglion cell intracellular Ca2+ levels by regulation of Ca2+ channel activity may be an important component of protective strategies for the treatment of retinal injury. Suppression of excessively elevated [Ca2+]i in ganglion cells would provide a temporal window for ganglion cell survival and axonal recovery following injury. Proposed studies will test the hypothesis that suppression of elevated [Ca2+]i following nerve injury enhances ganglion cell survival.
Specific aim 1 will define the signaling role of L- and T-type Ca2+ channels, and their accessory proteins (23 and 124) in mouse retinal ganglion cells. Experiments will determine a) the expression of L- and T-type Ca2+ channels and their accessory proteins by ganglion cells, and b) characterize the physiological and biophysical properties of L- and T-type Ca2+ currents of ganglion cells.
Specific aim 2 will test the hypothesis that ganglion cell Ca2+ signaling is dysregulated immediately following and several days after optic nerve crush or transection. Investigations will determine if there are short (12 and 24 hours)- and long (10 and 20 days)-term alterations of a) the expression of L- and T-type, and 23 and 124 Ca2+ channel subunits by ganglion cells, and b) membrane mechanisms that mediate Ca2+ currents and signaling in ganglion cells following optic nerve injury.
Specific aim 3 will test the hypothesis that Ca2+ channel antagonists and small interfering RNA (siRNA) antisense Ca2+ channel subunit vectors regulate Ca2+ signaling, and enhance ganglion cell survival after optic nerve injury. Investigations will determine if a) the L- and T-type Ca2+ channel antagonist, lomerizine, and b) antisense T-type (CaV3.1 and CaV3.2), and 23 and 124 Ca2+ channel subunit siRNA vectors, modulate Ca2+ signaling and enhance ganglion cell survival following optic nerve injury. Proposed studies will elucidate Ca2+ signaling in normal and injured ganglion cells, and develop novel approaches for controlling elevated intracellular Ca2+ following nerve injury, which will enhance ganglion cell survival, a key step in saving vision. These studies are consistent with the health-related goals of the Veterans Adminstration to develop highly effective and novel treatments for eye injury and disease.

Public Health Relevance

Project Narrative Traumatic brain injury (TBI) is a common casualty in the battlefield. Ocular trauma frequently occurs with TBI, which results in visual impairments, including acuity loss and blindness often due to optic nerve and retina injury. This Merit Review application will test the hypothesis that suppression of elevated intracellular Ca2+ induced by nerve injury enhances ganglion cell survival, a key step in saving vision. Planned studies will use animal models of ocular nerve injury and test novel strategies for controlling Ca2+ signaling using Ca2+ channel antagonists and antisense siRNAs for Ca2+ channels to reduce ganglion cell loss, thus setting the stage for developing new therapeutic approaches to ameliorate ocular damage and vision. These investigations are consistent with the health-related goals of the Department of Veteran Affairs to develop highly effective treatments for eye injuries and disease, and to prevent impaired vision and blindness.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000764-02
Application #
8278451
Study Section
Neurobiology C (NURC)
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
Indirect Cost
Name
VA Greater Los Angels Healthcare System
Department
Type
DUNS #
066689118
City
Los Angeles
State
CA
Country
United States
Zip Code
90073