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Targeting the Genetic and Molecular Role of ABCG2 Following Traumatic Brain Injury

Adams, Solomon (2018) Targeting the Genetic and Molecular Role of ABCG2 Following Traumatic Brain Injury. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Adams, Solomonsadams2013@gmail.comsoa180000-0002-5583-0322
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairEmpey, Philippempey@pitt.edupempey
Committee MemberConley, Yvetteyconley@pitt.eduyconley
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyac
Committee MemberKochanek, Patrickkochanekpm@ccm.upmc.edupak6
Committee MemberMa, Xiaochaomxiaocha@pitt.edumxiaocha
Date: 5 April 2018
Date Type: Publication
Defense Date: 6 March 2018
Approval Date: 5 April 2018
Submission Date: 4 April 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 204
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ABCG2, TBI, Transporters, Pharmacogenomics, Neurology
Date Deposited: 05 Apr 2018 15:27
Last Modified: 05 Apr 2018 15:27
URI: http://d-scholarship.pitt.edu/id/eprint/33837

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