TITLE
Mechanisms of protection from noise-induced hearing loss
ABSTRACT
The cellular and molecular bases underlying noise-induced hearing loss (NIHL), the second leading cause of
hearing loss globally, are to date, not understood presenting a barrier to the prediction of risk, the prevention, and
ultimately the treatment of this debilitating disease. 1.1 billion young people (aged between 12-35 years) are at
risk of hearing loss due to exposure to noise in recreational settings. Among Service Members of Operation
Enduring Freedom and Iraqi Freedom, NIHL and its associated tinnitus are the top two diagnoses and
unaddressed hearing loss poses an annual global cost of $750 billion US dollars. Noise attenuation and hearing
aids currently represent the only measures for protection and treatment, respectively. It is now clear that cochlear
synaptic loss precedes hair cell loss at low-moderate noise exposures (nonexplosive) effectively silencing affected
neurons. Our laboratory and others have illuminated genetic mechanisms that modify sensitivity to NIHL in mice
and humans. Through mouse GWAS we have identified a critical gene, Prkag2 encoding the g2 subunit of the
AMPK complex. We find that damaging noise leads to nuclear AMPK activity specifically in inner hair cells and
that Prkag2 deficient mice are susceptible to NIHL due to greater instability of the inner hair cell presynaptic ribbon.
There is an urgent need to identify directed therapies aimed at the prevention and/or repair of cochlear damage
from noise exposure, for which an understanding of the underlying mechanisms is an obligate prerequisite. Toward
the long-term goal of developing targeted therapies for the prevention and/or correction of noise-induced
synaptopathy, we now seek to decipher the pathways and mechanisms linking nuclear AMPK activity in inner hair
cells to NIHL. Based upon our preliminary data, our central hypothesis is that AMPK becomes activated and
trapped in the nucleus of inner but not outer hair cells by intranuclear phosphorylation after noise exposure and
subsequently regulates the expression of downstream targets that impact the number and volume of presynaptic
ribbons. Using a combination of genetics, physiology, cell biology, biochemistry, and structural biology, we
propose the following three aims: the identification of cellular factors associated with susceptibility to NIHL (Aim
1), the molecular basis of nucleocytoplasmic shuttling of AMPK (Aim 2), and the identification of additional factors
in the AMPK pathway leading to susceptibility to NIHL (Aim 3). As the AMPK pathway is fundamental to cell
survival, metabolism, gene regulation, and hearing, and is targetable, the completion of these aims has the
potential to lead to meaningful interventions for this debilitating condition.