Author Type

Graduate Student

Date of Award

Spring 5-2-2022

Document Type

Thesis

Publication Status

Version of Record

Degree Name

Master of Science (MS)

Department

Biological Sciences

First Advisor

Gregory Macleod

Abstract

Worldwide, the medical community struggles to identify undiagnosed diseases in nearly 25 million patients per year. Even with advances in medical research, physicians cannot determine the mechanisms by which these disorders progress within patients, resulting in a lack of proper treatment. A recent study identified patients who passed away with symptoms of hypotonia and lactic acidosis while having specific mutations in the mitochondrial enzyme, malate dehydrogenase (MDH2). Yet, little is known about the way in which such disorders arise from MDH2 mutations. Intriguingly, the mutations led to destabilization in hypoxia-inducible factor 1-alpha (HIF-1α). Using the CRISPR-Cas9 gene editing technique, we recapitulated the same MDH2 mutations in Drosophila. This allows us to investigate the link between MDH2 and HIF-1α through quantification of HIF-1α’s activation in relation to the Drosophila’s disease progression. Our ability to interrogate specific aspects of disease pathology in this model system provides exciting opportunities for developing therapeutic approaches.

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