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.
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.
