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.
TBI is contributing factor to a third (30.5%) of all injury-related deaths in the USA. The development of both cerebral edema and cell death are considered as major cause of neurological deficits and mortality in TBI patients. The present proposal will investigate how inactivation of a key pro-survival protein Akt by hydrogen sulfide underlie several secondary mechanisms associated with TBI pathology and based on this mechanism a novel therapeutic approach targeting Akt-sulfhydration will be developed that will improve neurological outcomes in TBI patients.
|Saha, Pampa; Gupta, Rajaneesh; Sen, Tanusree et al. (2018) Activation of cyclin D1 affects mitochondrial mass following traumatic brain injury. Neurobiol Dis 118:108-116|
|Sen, Nilkantha (2018) ER Stress, CREB, and Memory: A Tangled Emerging Link in Disease. Neuroscientist :1073858418816611|
|Sen, Tanusree; Saha, Pampa; Sen, Nilkantha (2018) Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-?. Sci Signal 11:|
|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|