Graduation Year

2021

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Engineering

Major Professor

Robert Frisina, Ph.D.

Co-Major Professor

Nathan Gallant, Ph.D.

Committee Member

William E. Lee III, Ph.D.

Committee Member

Mark Jaroszeski, Ph.D.

Committee Member

Bo Ding, Ph.D.

Keywords

D-methionine, Mechano-acoustic stimulation, NT3, PFT-alpha, Sensorineural hearing loss

Abstract

Sensorineural hearing loss (SNHL) is a prevalent neurodegenerative disorder often involving permanent damage and loss to the inner ear’s mechano-sensory hair cells and spiral ganglion neuron fibers. Significant causes of SNHL are ototoxic drugs, environmental factors, loud noises, and continuous wear with age. A successful but ototoxic chemotherapeutic known as Cisplatin often damages auditory hair cells via mitochondria dysfunction, DNA fragmentation, and cellular death through apoptosis. Despite the high prevalence of SNHL, there currently is no FDA-approved prevention or cure. Thus, auditory and cancer researchers have investigated various individual otoprotective agent preventions with limited success. This dissertation used a novel combinatorial approach of an anti-oxidant, a p53 inhibitor, and a neurotrophin to address cisplatin-induced hearing loss in two clinically relevant models. In an in vitro HEI-OC1 cellular study, significant protection resulted amongst the pre-treated groups with our combinatorial agents before cisplatin incubation. More specifically, HEI-OC1 cells that were pretreated with the cocktail of biotherapeutics significantly increased cell viability, lowered the amount of positive DNA fragmentation, and protected apoptotic activation in the presence of Cisplatin. In an organ of Corti ex vivo study, significant protection from hair and neuronal cell loss stemmed from our combinatorial approach prior to cisplatin administration. The multiple effects of Cisplatin present a challenging problem for a distinct cure to SNHL. The findings in this dissertation suggest a combinatorial approach to address these diverse, overlapping pathways, which could prove an adequate prevention or treatment option for SNHL in the future.

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