Traumatic Brain Injury (TBI) is a major cause of morbidity and mortality and it affects more than 1.7 millionpeople in the USA per year. TBI is multifactorial in nature however cerebral edema with robust inflammatoryresponses remains the most significant predictor of outcome of TBI. A critical barrier to progress in treating TBIis the absence of effective neuro-protective therapeutics. Most of the neuro-protective drugs tested in micehave failed in human clinical trials because they target a single factor, which mediates secondary injury in TBI.Our compelling preliminary data suggests that inactivation of a key survival protein Akt, by a gasotransmitter,hydrogen sulfide is responsible for outcomes associated with TBI. TBI-induced increase in hydrogen sulfidecauses sulfhydration of Akt (Akt-SSH) which leads to inactivation of its catalytic activity and stimulates severalsecondary outcomes that leads to neurobehavioral impairment following TBI. Based on our data the centralhypothesis is that in addition to neuroprotection, inhibition of Akt-sulfhydration stimulates neurogenesis andimproves neurological outcomes to promote functional recovery after TBI. To test our hypothesis in SpecificAim 1 we will determine how TBI induced Akt-sulfhydration affects Akt activity.
In specific Aim 2 we willdetermine whether prevention of Akt-sulfhydration improves TBI-pathology, and in specific aim 3 we will studyhow Akt-sulfhydration impacts neurogenesis, spine density and cognitive impairment following TBI. Therefore,investigating the potential of inhibition of Akt-sulfhydration in TBI is a novel proposal with clinical implicationsand translational value. Successful accomplishment of this project will show the feasibility of a new treatmentparadigm for TBI, introducing the concept that reduction in the level of Akt-sulfhydration acceleratesneuroprotection, neurorepair and reduces disabilities in TBI survivors.
TBI is contributing factor to a third (30.5%) of all injury-related deaths in the USA. The development of bothcerebral edema and cell death are considered as major cause of neurological deficits and mortality in TBIpatients. The present proposal will investigate how inactivation of a key pro-survival protein Akt by hydrogensulfide underlie several secondary mechanisms associated with TBI pathology and based on thismechanism a novel therapeutic approach targeting Akt-sulfhydration will be developed that will improveneurological outcomes in TBI patients.
