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Tonotopy in Acute Aminoglycoside-induced Metabolic Changes and Vulnerability of Cochlear Outer Hair Cells: An ODE-based Mathematical Modeling Analysis
aminoglycoside,tonotopic ototoxicity,outer hair cell,ATP,dynamic mathematical modeling,
|Publication Year :||2021|
Aminoglycosides, though life-saving and efficient antibiotics, are infamous for their ototoxicity by causing irreversible damage to the cochlear sensory cells. This ototoxicity is known for its tonotopically differential vulnerability in the cochlear: high-frequency, basal turn outer hair cells (OHCs) are preferentially affected. Previous experimental findings suggest that different metabolic biases may vary OHCs’ susceptibility, however, the metabolic mechanisms underlying this high-to-low-frequency propensity are still not fully understood. In this study, we performed in silico experiments to simulate metabolic variations induced by gentamicin (the most commonly prescribed aminoglycoside) in basal and apical OHCs separately. We built a kinetic-metabolic model based on a neuronal-model framework including glycolysis, citric acid cycle, oxidative phosphorylation, ROS production and scavenging systems. Original pathways were modified and new pathways were incorporated to depict hair cell metabolism. The proposed model was then calibrated onto existing experimental data in the literature. Our result of the modeling is that after gentamicin administration, basal turn OHCs suffer from a higher degree of ATP depletion, which correlates with their higher vulnerability to gentamicin.
|Appears in Collections:||物理學系|
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