Each year in the U.S., approximately 2.5 million people suffer traumatic brain injuries (TBIs). About 50,000 of these injuries will result in death, and more than 80,000 will lead to permanent disability. TBI is a chronic health condition and appears to be a notable risk factor for developing age-related cognitive impairment through converging biological mechanisms that are poorly understood.
Aric F. Logsdon, Ph.D., from the Department of Pharmacology and Neuroscience at the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine, said people with a history of TBI often present with vascular dysfunctions that are associated with age-related diseases.
The pathophysiological mechanisms associated with the onset and progression of age-related diseases, and potential impacts of TBI on aging, are not completely understood. Uncovering these mechanisms could lead to new clinical methods capable of reducing the development of age-related disease.
Supported by a three-year, $578,211 grant from the National Institutes of Health-National Institute on Aging, Logsdon will study how brain endothelial cells, or blood vessels within the brain, handle the stressors of neuroinflammation.
Neuronal cells use a mechanism called deubiquitination to maintain homeostasis, which is a cell's inherent ability to remain stable under inflammatory conditions. Logsdon said that when protein homeostasis is maintained, the cell is "happy." Neurons express a great deal of ubiquitin C-hydrolase (UCH), which removes ubiquitin from proteins to maintain cellular homeostasis. UCH is an acute blood-based biomarker for the indication of TBI severity.
The focus of my grant is on the vascular side of UCH function. While we understand a great deal about the UCH mechanism of neuronal homeostasis, less is understood about this process in the brain endothelial cells, or the brain's blood vessels."
Aric F. Logsdon, Ph.D., Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine
Endothelial cells function as a natural barrier between the bloodstream and tissues and help to regulate vascular homeostasis and inflammation. Very few studies have focused on the mechanistic role of deubiquitination on neurovascular function.
Under inflammatory conditions, such as a TBI event, noxious factors, such as prostaglandins, are released within the brain that inhibit normal UCH functioning, thereby disrupting homeostasis. The first aim of this grant looks to normalize the disruptive effects of prostaglandin on UCH function using an FDA-approved drug known as indomethacin.
"Whereas prostaglandin production is known to disrupt vascular homeostasis, and because UCH function is inhibited, in part, by prostaglandins that are released under inflammation, we seek to explore the role of prostaglandin-UCH interactions on TBI-induced vascular dysfunction," Logsdon explained.
Logsdon said the second aspect of the grant is to use mice that were generated by Steven H. Graham, M.D., Ph.D., from the University of Pittsburgh that have a mutation in the UCH protein that makes it prostaglandin resistant. Graham has graciously provided the UCH mutant mice to Logsdon for the completion of the studies outlined in this award.
"There are reports of UCH mutant mice being protected from neuroinflammation, with their cognitive function being preserved after stroke and TBI," Logsdon said. "However, no one has explored vascular function in these UCH mutant mice."
In addition, there is an underlying aspect that Logsdon will study with this grant. Historically, the UCH activity in neurons has focused on protein homeostasis.
"My lab focuses on brain sugar composition and how sugars are differentially processed within the brain under normal and aging conditions," Logsdon said. "Under inflammatory conditions, sugars are aberrantly processed and may even accumulate to disrupt cellular homeostasis - much like how proteins accumulate in neurocognitive disorders, such as Alzheimer's disease."
In previously published research, Logsdon discovered that sugars are processed differently in the brains of humans with Alzheimer's disease. Brain tissues from these individuals show an abnormal sugar patterning when compared to non-cognitively impaired humans.
Logsdon also has reported that a similar sugar pattern was demonstrated in the brains of mice exposed to TBI. He said the clinical relevance of aberrant sugar processing in TBI and Alzheimer's disease may suggest brain sugar accumulation as an early driver of cognitive impairment, and that under injury conditions, relieving the brain from sugar accumulation should help to reduce the burden of chronic inflammation. As such, Logsdon is focusing on the mechanism of aberrant sugar production and accumulation as a novel mechanism of TBI-related cognitive impairment.
"I think the sugars are accumulating over time, in part, through this aforementioned UCH system," Logsdon said. "That's the goal of this research: to block the UCH system and determine whether we observe proper brain sugar processing and an improvement in neurovascular function in mice exposed to TBI. We predict that a functional UCH system will drive normal sugar processing in the brain and thereby maintain the integrity of the blood-brain barrier, even after TBI.
"If we can successfully block prostaglandin-related vascular dysfunction, and - in using the UCH mutant mice - we can show that sugars are processed normally and not accumulating in the brain, we may have discovered aberrant sugar processing as a novel therapeutic target for TBI, and possibly for Alzheimer's disease as well."
Understanding the human brain architecture through gene coexpression analysis