Dissertation/Thesis Abstract

Targeting the Genetic and Molecular Role of ABCG2 Following Traumatic Brain Injury
by Adams, Solomon M., Ph.D., University of Pittsburgh, 2018, 205; 11003751
Abstract (Summary)

Traumatic brain injury (TBI) is a leading cause of death and disability. Despite its overwhelming burden on sufferers, their families, and the health-care system; there are no pharmacologic treatments that improve long term clinical outcomes. Drug development for TBI has focused on mitigation of factors that contribute to the persistent secondary injury from TBI. These target reactive oxygen species generation, cerebral edema, excitotoxicity, among others. Genomics has been a productive area to support TBI drug development, and pharmacogenomics (PGx) - based drug use and development has gained utility in critical care and TBI. This helps to identify new targets for treatment and/or prognostication, and to provide targeted therapy based on an individual’s genomics. Our objective was to evaluate the role of drug transporters, particularly the ATP-Binding Cassette transporter, ABCG2, following severe TBI. We measured expression of transporters in experimental TBI, evaluated the association of a missense genetic variation in ABCG2 with clinical outcomes from TBI, and studied the change in disposition of the ABCG2 substrate, uric acid (UA), in patients with TBI. We found that overall transporter expression tended to decreased acutely following TBI, exemplified by ABCG2 expression, which was significantly decreased early following injury with a rapid return to baseline. The missense variation in the ABCG2 gene, c.421C>A, was found to be associated with improved outcomes following severe TBI in younger patients, suggesting that ABCG2 dysfunction is neuro-protective. Finally, we discovered that patients with severe TBI who carry a variant allele at ABCG2 c.421C>A have measurable decrease in UA transport in the CNS. These findings suggest that UA is protective following TBI, which may be related to its role as an antioxidant. Future study in this area can include further development of animal models for TBI that can mimic human levels of UA, which are about 10-fold higher in humans than in most other mammals. They may also include prospective observational trials to validate the findings of UA’s association with ABCG2 and outcomes. Clinical trials of therapeutic UA or the UA precursor, inosine, may also be warranted in patients suffering from severe TBI.

Indexing (document details)
Advisor:
Commitee:
School: University of Pittsburgh
Department: Pharmacy
School Location: United States -- Pennsylvania
Source: DAI-B 80/02(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Neurosciences, Genetics, Pharmaceutical sciences
Keywords: Abcg2, Pharmacogenomics, Transporters, Traumatic brain injury, Uric acid
Publication Number: 11003751
ISBN: 9780438573376
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