Sen Brain Trauma Laboratory

The focus of the Sen Brain Trauma Laboratory, directed by Nilkantha Sen, PhD, at the University of Pittsburgh Department of Neurological Surgery is to elucidate the underlying molecular and cellular mechanisms responsible for numerous secondary mechanisms associated with traumatic brain injury (TBI) which leads to cognitive dysfunction and other long-term post-traumatic disorders including anxiety, depression and visual impairments. Our study provides a novel platform to design more effective therapeutic interventions to improve neurobehavioral outcomes following TBI.

Traumatic brain injury (TBI) is one of the leading cause of morbidity and mortality in humans and it affects more than 1.7 million Americans each year. The economic burden of taking care of TBI-patients exceeds more than 78 billion in 2014. The most serious aspect of TBI is that of cognitive impairment as evidenced by animal and clinical studies focusing on synaptic plasticity and memory. In addition, depression and anxiety-like behavior are a common problem after TBI, with a recent study in one cohort of TBI patients finding that 53.1% had at least one episode of major depressive disorder in the year following injury. The enduring neurobehavioral deficits resulted from several factors including the mitochondrial dysfunction, lack of neurotrophic factors, impairment in neurogenesis, axonal myelination, and the deficiency in synaptic pruning after TBI.

Recent findings suggest that an inactivation of a key protein kinase Akt is responsible for cell death and an activation of a transcription factor, Foxo3a causes an induction of AQP4 which contributes to edema following TBI. In another effort, research has shown that administration of an HIF1α activator, DMOG regulates angiogenesis and provides neuroprotection following TBI. An induction of ER stress and oxidative stress is known to contribute memory impairment following TBI. However, the mechanism was not elucidated before. Research at the Sen Lab has shown that phosphorylation of an ER stress marker, PERK inactivates transcriptional activity of CREB and degrades PSD95 that results in a reduction in synaptic density and memory impairment. These studies provide a new insight into understanding a few aspects of TBI; however, the Sen Lab continues to study the underlying mechanisms responsible for other secondary mechanisms following TBI. In particular, the Sen Lab is in the process of identifying the central mechanism which can regulate multiple factors which contribute significantly long-term outcomes following TBI.

In addition to these efforts, the laboratory has been studying the role of gaseous neurotransmitters such as hydrogen sulfide (H2S) and nitric oxide (NO) in the pathology associated with brain injury or neurodegeneration. Recently, research has shown that an aberrant nitrosylation of GAPDH protein contributes to tauopathy while sulfhydration of the same protein contributes to the synaptic dysfunction upon an induction of inflammation in the diseased brain. Since both nitrosylation and sulfhydration of GAPDH can be targeted by a small compound CGP3466B, we are in the process of testing this compound in a large scale.

For a detailed publication list, please visit Dr. Sen's publications on the the National Library of Medicine's publication database website.