Targeting endoplasmic reticulum (ER) stress and restoring ER homeostasis in pediatric traumatic brain injuries.
Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide and affects more than 1.7 million Americans each year. TBI can happen to anyone, but children age 0-4 year old are at the highest risk. The pathobiology of the response to biomechanical injury in a developing brain is distinct from that in adults. TBI in young children often interrupt normal brain development and cause significant deficits in cognition, social performance and mood regulation that persist into adulthood. These long-term neurocognitive impairments are not greatly helped by current cognitive training and pharmacologic treatments. Therefore, it is crucial to discover age-specific approaches for the treatment of pediatric TBI. Endoplasmic reticulum (ER) stress has recently received increased attention in the pathogenesis of various diseases, especially neurodegenerative diseases. ER stress is induced by the accumulation of unfolded and misfolded proteins in the ER lumen, which activates unfolded protein response (UPR) signal pathway to restore ER homeostasis. However, overwhelming ER stress can cause UPR failure and lead to cell apoptosis. ER stress has been seen in adult postmortem human brains diagnosed with chronic traumatic encephalopathy, and also has been shown to be responsible for the functional deficits in adult rodent TBI. Our team will investigate the physiological role of ER homeostasis by applying genetic mouse models with defects in critical ER protein quality control pathways in a pediatric TBI model, and further evaluate the efficacy of nanotechnology–guided drug delivery for the treatment of ER stress in pediatric TBI.
Published in Diabetes
Presented at the 2019 Midwest DDRC Workshop at the University of Chicago, Chicago, IL