MOLECULAR MECHANISMS OF DRUG- AND NOISE-INDUCED HAIR CELL DEATH AND PROTECTION
Uribe, Phillip M.
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Hearing loss is a common, debilitating disorder that often leads to social isolation and depression. The prevalence of hearing loss remains high (15%) due to a lack of adequate tools to prevent it. Hearing loss commonly results from damage or loss of sensorineural hair cells within the inner ear. Hair cells are responsible for transforming mechanical wave energy into electrochemical potentials. In humans, exposure to certain classes of drugs (e.g., aminoglycosides) or excessive noise are known to cause damage to hair cells and subsequently decrease sensitivity to sound. The first purpose of this dissertation was to evaluate the potential otoprotective effects of the hepatocyte growth factor mimetic MM-201 as well as determine its mechanism of action. The second purpose was to develop a novel acoustic trauma model for the zebrafish lateral line to expand our understanding of noise-induced hair cell loss and accelerate drug discovery efforts to prevent acoustic trauma. Chapter 2 shows that treatment with MM-201 prevented aminoglycoside-induced hair cell death in the zebrafish lateral line in a dose-dependent manner. MM-201 protection operated entirely through activation of the HGF receptor and partially relied on downstream targets of HGF signaling (MEK, AKT, and TOR). Chapter 3 examined the protective effect of MM-201 on mammalian hair cells using the adult utricular explant model of ototoxicity. MM-201 conferred protection on utricular explant hair cells and MM-201 did not alter the bactericidal efficacy of aminoglycosides at therapeutically relevant concentrations. Chapters 2 and 3 collectively indicate that MM-201 is a strong clinical candidate as a hair cell protectant against aminoglycoside ototoxicity. Chapter 4 shows that ultrasonic cavitation damages zebrafish lateral line hair cells in an exposure time-, post-exposure time-, and intensity-dependent manner. Cavitation resulted in hair cell-specific damage that was dependent on functional mechanotransduction. Finally, cavitation-induced hair cell damage could be prevented by pharmacological inhibition of reactive oxygen species, demonstrating a conserved mechanism of action with mammalian models of acoustic trauma. Chapter 4 demonstrates that cavitation damages zebrafish hair cells in a manner reminiscent of acoustic trauma-induced mammalian hair cell damage, suggesting zebrafish are a tractable model for the study of acoustic trauma.