Date of Award

2021

Embargo Period

8-1-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Stephen Duncan

Second Advisor

Cynthia Wright

Third Advisor

Robin Muise-Helmericks

Fourth Advisor

Mindy Engevik

Abstract

Mitochondrial DNA Depletion Syndrome 3 (MTDPS3) is the most common mitochondrial DNA (mtDNA) depletion syndrome. MTDPS3 is an autosomal recessive disorder caused by a mutation in the deoxyguanosine kinase (DGUOK) gene in which a reduction in mtDNA nucleotides results in decreased levels of Adenosine Triphosphate (ATP). The DGUOK phenotypes vary; however, liver dysfunction tends to be consistent for all pediatric patients. Liver transplants can be beneficial; however, it’s only a palliative treatment at best, and the affected population rarely reaches adulthood. This thesis describes a high-throughput drug screen to identify a potential therapy for MTDPS3. MTDPS3 mutant hepatocytes derived from induced pluripotent stem cells (iPSCs) were utilized in the drug screen of the South Carolina Compound Collection (SC3) library. From the primary screen of 10,000 compounds, 63 compounds increased ATP levels at a sample number of one. The primary hits were used to perform biological replicates with the knockout cells, and six can increase ATP levels consistently. Two of the six compounds increased ATP production at eight different drug concentrations. My results show six small molecules with the therapeutic potential to treat an MTDPS3 phenotype in-vitro.

Rights

All rights reserved. Copyright is held by the author.

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