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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094516-06
Application #
9903469
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
2017-04-03
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260
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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
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