The Epichaperome: A Novel Therapeutic Target for Blast Traumatic Brain Injury
Abstract
Exposure to blast waves during training or deployment can affect the brain. Blast traumatic brain injury of all severities can result in chronic disturbances of cognitive, behavioral, emotional, and physical functioning. Normal complex cognitive function requires optimal functioning of neuronal networks. It has been well documented that, when the brain undergoes stress (e.g., stroke, neurodegeneration, trauma), heat shock proteins are induced to assist in protein folding, degradation and other functions. Also called chaperones, they function to maintain cellular function by aiding in protein folding, activation, degradation, or disaggregation in normal cells. Chaperomes are composed of chaperones, co-chaperones, and other factors and function to modulate the structural and functional architecture of protein networks. Under conditions of cellular stress, the chaperomes become biochemically rewired to form a network of stable, high-molecular-weight complexes, recently called epichaperomes. It has recently been demonstrated that the epichaperomes are responsible for the disturbance of protein-protein interaction networks which ultimately become dysfunctional and can drive brain pathology. These epichaperome mediated protein network changes have been identified and therapeutically targeted. Inhibition of epichaperomes result in the degradation of disease-causing proteins and normalization of affected cellular regulatory pathways. A member of a new class of drugs called epichaperome inhibitors, PU-AD is an oral, brain-permeable inhibitor of heat shock 90 in epichaperomes. PU-AD has been shown to reduce the epichaperome in models of Alzheimer’s disease and Parkinson’s disease. We have preliminary data that PU- AD treatment can attenuate cognitive deficits after experimental traumatic brain injury. It is currently unknown whether blast TBI results in the formation of epichaperome responses. The overall goal of the project is to provide proof of principle that blast TBI produces an epichaperome response and that the anti-epichaperome drug PU-AD reverses epichaperome levels and improves learning and memory. The project will first define the time course of epichaperome formation after experimental blast. Next, we will test the efficacy of PU-AD therapy on cognitive function after experimental blast. If epichaperomes are determined to result from blast TBI, a novel therapeutic target will be identified that could benefit survivors of blast traumatic brain injury. The project focus area of Treat and the sub-focus area of Treatments that promote functional recovery, including interventions administered acutely, during the post-acute phase, or during the chronic phase of injury. The epichaperome is a novel mechanism for aberrant brain function after blast traumatic brain injury. Therapies, such as PU-AD are already being evaluated clinically for other brain disorders and could rapidly be translated to treat military personnel with brain injuries resulting from blast exposure.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310400
Entities
People
- Clifton Dixon
Organizations
- United States Army