Traumatic Brain Injury (TBI) affects about 1.7 million people in the US per year. More than 47% of total injured population had non-superficial eye injuries and a large subset of this population is under the risk of blindness. TBI-induced increase in visual problems includes binocular vision dysfunction, light sensitivity, photophobia and visual field defects. These are often associated with deficiency in both acute and chronic PERG responses due to damage to retinal ganglion cells (RGC). The pathophysiology of these injuries is not well understood but impacts negatively the daily living activities of our soldiers and veterans. We hypothesize that TBI-dependent severe RGC death and subsequent deficiency in PERG and vision disturbances can be ameliorated or prevented by inhibiting Brn3a-sulfhydration (Brn3a-SSH), the key mechanism responsible for degradation and inactivation of Brn3a. The hypothesis is based on our recently published data showing that CBS is highly enriched in RGC and our compelling preliminary data showing that TBI leads to increased RGC death concomitant with degradation of sulfhydrated Brn3a through its interaction with an E3 ligase Siah. In CBS heterozygous mice (cbs+/-) or administration of sulfhydration mutant of Brn3a, (Brn3a-C406S), TBI-induced RGC cell death was reduced significantly. We outline three Specific Aims to test the above hypotheses:
Aim 1 Test the hypothesis that TBI leads to Brn3a-sulfhydration via modulation of CBS expression and intracellular H2S levels.
Aim 2 : Test the hypothesis that Brn3a-sulfhydration triggers RGC death following TBI.
Aim 3 : Test the hypothesis that reducing Brn3a-sulfhydration rescues TBI-induced functional and structural alterations in RGC. Accomplishing these aims will lead to a clearer understanding of the mechanism(s) by which Brn3a- sulfhydration contributes to induction of RGC loss following TBI. Given the impact of inactivation of Brn3a on induction of RGC loss after TBI, preventing Brn3a-sulfhydration will have far-reaching translational implications.

Public Health Relevance

Hydrogen sulfide (H2S) is a gasotransmitter and has been implicated in various neurological disorders and stroke. The focus of the research is to understand how elevation in the level of H2S influences vision impairment after traumatic brain injury (TBI). TBI is a major cause of morbidity and mortality and it affects more than 1.7 million people throughout USA. More than 47% of total injured population had non-superficial eye injuries and a large subset of this population is under the risk of blindness. We will use mouse models which minimize the elevation of H2S after TBI due to partially lacking of enzyme and we will determine the mechanism by which H2S leads to structural and functional alteration in vision after TBI.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY025622-01A1
Application #
9106173
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Sen, Nilkantha (2017) An insight into the vision impairment following traumatic brain injury. Neurochem Int 111:103-107
Sen, Nilkantha (2017) Functional and Molecular Insights of Hydrogen Sulfide Signaling and Protein Sulfhydration. J Mol Biol 429:543-561
Sen, Tanusree; Gupta, Rajaneesh; Kaiser, Helen et al. (2017) Activation of PERK Elicits Memory Impairment through Inactivation of CREB and Downregulation of PSD95 After Traumatic Brain Injury. J Neurosci 37:5900-5911
Sen, Tanusree; Sen, Nilkantha (2016) Treatment with an activator of hypoxia-inducible factor 1, DMOG provides neuroprotection after traumatic brain injury. Neuropharmacology 107:79-88
Sen, Tanusree; Sen, Nilkantha (2016) Isoflurane-induced inactivation of CREB through histone deacetylase 4 is responsible for cognitive impairment in developing brain. Neurobiol Dis 96:12-21
Gupta, Rajaneesh; Sen, Nilkantha (2016) Traumatic brain injury: a risk factor for neurodegenerative diseases. Rev Neurosci 27:93-100