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Biology subjects

Sowell, K. M.

Publications and source records attributed to Sowell, K. M..

2 recordsLinked to original sources

Distinct effects of Atg3 and Atg10 on Autophagosome Formation in Yeast

Autophagosome formation involves two E2 enzymes: Atg3, which conjugates Atg8 to the lipid phosphatidylethanolamine, and Atg10, which conjugates Atg12 to Atg5. Although both are required for autophagy, it is unclear exactly what roles these pathways play in the process of autophagosome formation. We used baker's yeast expressing mutant versions of both Atg3 and Atg10 that reduce, but do not eliminate, their activity to better understand their effects on Atg8 lipidation, autophagic flux, and the size and number of autophagosomes formed during nitrogen starvation. We found that while Atg3 primarily affects Atg8 lipidation and autophagosome size, Atg10 has less of an effect on Atg8 lipidation and primarily controls autophagosome number. This demonstrates that these two enzymes have distinct mechanistic roles in autophagosome formation, and implies an as-of-yet undiscovered function for the Atg12-Atg5 conjugate.

cell biology↗

FDA-approved drug repurposing in zebrafish identifies thyroid hormone and other compounds as potential antithrombotics

Venous thromboembolism (VTE) is a highly prevalent medical condition with limited therapeutic options and an incomplete understanding of its acquired and inherited subtypes. The zebrafish is a model with the benefits of external development, fecundity, optical transparency, and hemostasis that demonstrates conservation with mammals. We utilized zebrafish as a phenotypic screening tool to identify novel therapeutic options for preventing VTE. A library of FDA-approved compounds was screened for suppression of acquired (elevated estrogen) and spontaneous (protein C deficiency) thrombosis. We found that thyroid hormone, receptor tyrosine kinase (RTK) inhibitors, and proton-pump inhibitors (PPIs) effectively modulated levels of thrombosis, particularly in the estrogen-induced model. These also showed a more favorable hemostatic profile than standard therapies, suggesting alternative mechanisms. Genome editing of thyroid hormone receptor proved that thyroid hormone action is on target. A retrospective electronic health record (EHR) analysis found that thyroid-hormone prescriptions in hormonal contraceptive users correlated with a higher VTE risk, potentially limiting direct repurposing but highlighting thyroid signaling as a pathway involved in estrogen-induced thrombosis. Together, these data identify several drug classes that can be tailored to specific subtypes of VTE and help elucidate distinct pathways driving thrombosis.

pharmacology and toxicology↗