DOI
https://doi.org/10.25772/8BT6-P596
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Dayanjan Wijesinghe
Second Advisor
Joseph McClay
Third Advisor
Elvin Price
Fourth Advisor
Mohammad Alshabeeb
Fifth Advisor
MaryPeace McRae
Sixth Advisor
Patricia Slattum
Abstract
Background: Sickle Cell Disease (SCD) and related hypercoagulable conditions, particularly those with elevated von Willebrand factor (vWF) levels, pose significant health challenges globally, with a notable burden in Saudi Arabia. This dissertation investigates genomic data to identify novel therapeutic targets and drug repurposing opportunities for SCD and vWF-linked hypercoagulability.
Methods: The research consisted of three integrated studies: (1) a case-control Genome-Wide Association Study (GWAS) comparing Saudi SCD patients with healthy controls, (2) bioinformatic analysis of identified genes' druggability and their interaction with approved medications, and (3) analysis of vWF-linked hypercoagulability using public GWAS data. The studies utilized drug-gene interaction and protein structure databases to identify potential drug candidates.
Results: The GWAS identified significant genetic variants in Saudi SCD cases. Subsequent analysis revealed several approved medications suitable for repurposing, including simvastatin, allopurinol, and specific immunomodulators. Olfactory receptor gene clusters emerged as novel drug targets with high druggability scores. The vWF-linked hypercoagulability study identified additional candidates like nebivolol, pravastatin, riociguat, candesartan, and acetylcysteine, along with novel druggable targets such as CLEC4M and SLC44A2 involved in blood coagulation and vascular function.
Conclusion: This research establishes a framework for drug repurposing and novel drug discovery in SCD and related conditions. While the computational predictions are promising, clinical validation studies are necessary for practical implementation.
Rights
© Ali Alghubayshi
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-1-2024