The Role of the Mitogen Activated Protein Kinase Pathway in Cisplatin and Noise-Induced Hearing Loss

Hearing loss is one of the most common types of disability; however, there are few ways to combat it with only one FDA-approved drug to treat any type of hearing loss. Cisplatin, a commonly used chemotherapy agent, and exposure to loud noise are two main causes of hearing loss. There are many cellular pathways involved in both types of hearing loss and the mitogen activated protein kinase (MAPK) pathway is one. The MAPK pathway consists of a phosphorylation cascade with RAF, MEK1/2, ERK1/2 as the main three kinases that effect a multitude of cellular processes. The MAPK pathway has been associated with hearing loss; however, its exact role was not elucidated. This dissertation explores the exact role that MAPK activation has in hearing loss and identifies promising drug candidates to prevent these highly prevalent conditions. Genetically knocking down the MAPK pathway by utilizing KSR1 KO mice (scaffolding protein in the MAPK pathway) demonstrated that KO mice were resistant to both cisplatin and noise-induced hearing loss. Pharmacological inhibition of all three kinases in the pathway also protected mice from both cisplatin and noise-induced hearing loss. Dabrafenib, a BRAF inhibitor, and trametinib, a MEK1/2 inhibitor, protected from cisplatin-induced hearing loss in a translational mouse model of cisplatin ototoxicity while dabrafenib, trametinib, and tizaterkib, an ERK1/2 inhibitor, protected from noise-induced hearing loss. Additionally, dabrafenib was shown to be protective from another side effect of cisplatin, nephrotoxicity. Inhibiting the MAPK pathway decreased inflammation and immune cell infiltration following cisplatin administration and noise exposure which is a potential mechanism of protection. Furthermore, MAPK inhibition protected from outer hair cell death and synaptic dysfunction in the cochlea which suggests that preventing these cells from dysfunction is the main protective mechanism from hearing loss. This dissertation clearly demonstrates that inhibiting any of the kinases in the MAPK pathway protects from hearing loss and highlights dabrafenib as the most promising drug to repurpose for hearing protection. This data also distinguishes an important role of the MAPK pathway in the damage response for post-mitotic cells, such as cochlear or kidney cells, which could have wide-reaching implications in other diseases.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2024

Author dc:creator

• Lutze, Richard Dennis

Advisor dc:contributor.advisor

• Teitz, Tal

• Cisplatin
• Drug Repurposing
• Hearing Loss
• Inflammation
• MAPK Pathway
• Noise

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Repository record dc:identifier.uri

https://cdr.creighton.edu/handle/10504/153999

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/153999