A Bioinformatical Strategy for Repositioning Drugs as Countermeasures for Space Radiation
Creators: name: Diaz, Thomas
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2024

description: The exact health implications in humans after exposure to space radiation, primarily known as Galactic Cosmic Rays (GCRs), are largely unknown. Terrestrial analog studies in murine models using simulated GCRs allude to space radiation induced carcinogenesis and ocular, bone, central nervous system, immune system, and cardiovascular alterations. Understanding the effects of GCRs on the cardiovascular system are of particular interest due to potentially severe cardiac consequences to astronauts during long-duration spaceflight missions. Currently, there are no established pharmacological countermeasures for GCR exposure. Drug repositioning may be a favorable method of accelerating pharmaceutical research in the 
field of space medicine. This study aims to present a computational strategy for identifying drug 
candidates to be repositioned as countermeasures for space radiation using proteomic data from murine 
models exposed to a single dose of simulated GCRs.

This study is a secondary analysis utilizing proteomic data from a multi-omics study in the Bowles lab at 
Duke University. The top 20 differentially expressed proteins (DEPs) from murine heart tissue after 
exposure to 5-ion GCRs were mapped to their human orthologs. A protein-protein interactome (PPI) was 
created using a network-based approach and the nodes with the highest degree and betweenness centrality were identified for screening purposes. Functional enrichment analyses of the PPI were conducted to understand Gene Ontology (GO), pathways, and diseases within the network. A drug repurposing web tool was used to identify drug-target-disease interactions. A comprehensive list of drug candidates was extracted for screening and further analysis.

Of the top 20 DEPs, 18 have human orthologs. Among the 276 proteins in the PPI, the proteins with the 
highest betweenness centrality are EGFR, CALM2, CALM3, MYC, and TP53. The proteins in the PPI 
with the highest node degree are MYC, EGFR, ESR1, TP53, and JUN. The GO enrichment presents various biological processes, cellular components, and molecular functions that impact muscle contraction, cardiac function, and cardiac performance. The enriched pathways include hypertrophic 
cardiomyopathy, dilated cardiomyopathy, oxidative phosphorylation, adrenergic signaling in 
cardiomyocytes, diabetic cardiomyopathy, motor proteins, chemical carcinogenesis – reactive oxygen 
species, and thermogenesis among others. The enriched diseases include various forms of 
cardiomyopathy among others. The drug-target-disease network contains 1656 unique drug candidates.

The findings from this study corroborate the cardiac phenotype and proteomic findings from the Bowles 
lab’s previous publications. There are few studies that have explored pharmacological countermeasures 
for space radiation. The integration of a network-based approach using a computational strategy alongside functional enrichment analyses provides insight on potential mechanisms and targets of action involved in a cardiovascular response to GCRs. Ultimately, the drug candidates identified in this study may be screened for validation to further explore pharmacological countermeasures for space radiation to enhance the health and performance of those who undergo space flight.