Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

Su-Hua Sha

Second Advisor

Bradley Schulte

Third Advisor

Hainan Lang

Fourth Advisor

John Lemasters

Fifth Advisor

Joe Blumer

Sixth Advisor

Jochen Schact

Abstract

Noise-induced hearing loss (NIHL) is a major public health issue and an unresolved clinical problem. Here we investigate pathomechanisms of auditory sensory cell death and suggest a novel target pathway for intervention. Cellular survival from stress depends upon maintenance of energy homeostasis, largely by the adenosine monophosphate-activated protein kinase (AMPK) which coordinates metabolic pathways with the energy demands of the cell. In response to traumatic noise exposure which resulted in hair cell death, levels of p-AMPKα increased in hair cells in a noise intensity-dependent manner. Inhibition of AMPK via administration of siRNA or a pharmacological inhibitor attenuated noise-induced losses of hair cells and synaptic ribbons, and preserved auditory sensitivity. The phosphorylation of liver kinase B1 (p-LKB1), an AMPK kinase, was increased by noise exposure in cochlear tissues. Additionally, the phosphorylation of calcium-calmodulin kinases I and IV (p-CaMKI/IV), the targets of calcium-calmodulin kinase kinase beta (CaMKKβ), an alternative AMPK kinase that is mediated by calcium, was increased in outer hair cells (OHCs) after the exposure. Inhibition of LKB1 or CaMKKβ by siRNA or knockout mice reduced OHC loss and NIHL. Finally, the increased p-AMPKα in OHCs after noise exposure was attenuated by silencing LKB1 or using CaMKKβ knockout mice. These results indicate that noise exposure leads to hair cell death by activating AMPK via LKB1- and CaMKKβ-mediated pathways, facilitating the pathogenesis of NIHL.

Rights

All rights reserved. Copyright is held by the author.

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