Development of therapeutic strategy against TBI based on hydrogen sulfide

? DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) is a major cause of morbidity and mortality and it affects more than 1.7 million people in the USA per year. TBI is multifactorial in nature and characterized by cell death, edema, neurovascular injury, increase in blood brain barrier permeability, reduction in neurogenesis and neurological impairments. A critical barrier to progress in treating TBI is the absence of effective neuroprotective therapeutics. Most of the neuroprotective drugs tested in mice have 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 sulfide causes sulfhydration of Akt (Akt-SSH) which leads to inactivation of its catalytic activity and stimulates several secondary outcomes that leads to neurobehavioral impairment following TBI. Based on our data the central hypothesis is that in addition to neuroprotection, inhibition of Akt-sulfhydration stimulates angiogenesis/neurogenesis and improves neurological outcomes to promote functional recovery after TBI. To test our hypothesis in Specific Aim 1 we will determine how TBI induced Akt-sulfhydration affects Akt activity. In specific Aim 2 we will determine whether prevention of Akt-sulfhydration improves TBI-pathology, and in specific aim 3 we will study how 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 implications and translational value. Successful accomplishment of this project will show the feasibility of a new treatment paradigm for TBI, introducing the concept that reduction in the level of Akt-sulfhydration accelerates neuroprotection, neurorepair and reduces disabilities in TBI survivors.