Traumatic Brain Injury (TBI) & ER Stress

The impact of PERK on post-traumatic tauopathy in Alzheimer disease

 

     Approximately 320,000 military personnel have sustained a confirmed traumatic brain injury since deployment to Afghanistan and Iraq. In addition, 1.7 million United States citizens suffer TBI every year costing the American economy an estimated $22 million to maintain support for veterans and civilians. Greater risk is ensuing upon these patients as studies have linked TBI and Alzheimer’s disease (AD). One possible pathway is the association between TBI-induced tau pathology that is a major hallmark of AD brains. However, the molecular mechanism linking TBI, tau, and AD is not yet known. Current studies have shown that TBI induces endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR) and elicits induction of Protein Kinase R-like ER Kinase (PERK), an ER stress sensor. We determined that there is an association between the chronic activation of PERK and AD tau pathogenesis.

PERK inhibition for traumatic brain injury therapeutics

 

     Our overall objective is to determine the molecular mechanism by which traumatic brain injury (TBI) activates the endoplasmic reticulum (ER) stress sensor PERK (protein kinase R-like ER kinase) and leads to neurological dysfunction. Successful completion of this proposal will establish the PERK pathway as a novel therapeutic target for TBI. Finally, by completing these aims, we have already accrued to submit a VA Merit Award this September

     The overarching hypothesis of this proposal is that TBI activates PERK, which induces tau pathogenicity typical of AD. This hypothesis is being tested in two aims. Aim 1 will determine the extent to which TBI severity induces PERK activation in mice over time. The objective of this aim is to determine the duration and fluctuation of PERK activity after TBI as well as the extent of the affected brain area. The hypothesis of this aim is that TBI severity regulates the duration and distribution of PERK activity in the brain. The expected outcome is that that the severity of the injury will increase PERK activity in brain region correlating to degeneration. This aim will progress the understanding of TBI-induced ER stress.

Aim 2 will determine the effect of PERK modulation on tau pathology and brain function after TBI. The objective of this aim is to determine the impact of PERK activation and inhibition on tau pathology as well as brain function after a brain injury. The hypothesis is that PERK modulation not only will modify tau pathology but the cognitive consequences as well. The expected outcomes are that PERK activation (by means of genetic and chemical activation-Sub Aim 2.1), tau pathology, and cognitive impairments will be greater in the mice suffering from a TBI. However, PERK inhibition (also by means of genetic and chemical inhibition-Sub Aim 2.2) will attenuate the PERK expression, tau pathology, and brain dysfunction observed after a TBI.

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