Noise-induced hearing loss (NIHL) is a pervasive and growing health problem, yet knowledge of basic cellular processes involved in both NIHL and potential endogenous protective signaling systems remain incomplete. The initial, and still predominant, model of cochlear protection is based on olivocochlear system activity, but other signaling systems, including the hypothalamic-pituitary-adrenal (HPA) axis also have been suggested to protect the cochlea against acoustic injury. Significant, caveats have been raised concerning these two models of cochlear protection, however. The main issues of concern are the intensity and time of stimuli required to activate signaling, and the time course for protective effects to occur. Our recently published data indicate that the cochlea is under local neuroendocrine control. All major signaling molecules expressed along the classic HPA axis are also expressed and completely contained within cells in the cochlea. This data strongly suggests the existence of a locally active HPA-equivalent cochlear stress axis. Our preliminary data demonstrate that the cochlea is capable of releasing both corticosterone and aldosterone in response to corticotropin releasing factor (CRF) and adrenocorticotropin hormone (ACTH), both of which we have previously demonstrated to be expressed in the cochlea. We have also previously shown that CRF signaling plays an integral role in the coch- lea. Ablation of CRFR1 produces a 25dB loss of sensitivity, while ablation of CRFR2 generates a 20dB gain of sensitivity, while increasing susceptibility to ABR threshold shifts following exposures as low as 50dB SPL Given the caveats related to current models of cochlear protection with respect to their requirement for activa- tion by high intensity sounds, and our data suggesting the cochlear stress axis may be active at lower intensity sound exposures, we propose that this cochlear HPA-equivalent signaling system represents a novel, previ- ously unrecognized element involved in cochlear protection. To test whether the cochlea uses an HPA-like sig- naling system for protection, more information is required concerning the basics of the cochlear cellular stress axis. For example, it remains unproven whether the system is activated by sound, and whether its selective activation can protect against NIHL. These unknowns are impediments to a deeper understanding of cochlea signaling. Our hypothesis is that the cochlear stress axis acts as an independent local (fast responding) neuro- endocrine control system activated by sound that contributes to the modulation of sensitivity and stress- responses via local steroid hormone release following exposure to damaging stimuli. We will pursue two spe- cific aims, designed to: 1) identify cells in the cochlea that receive CRF signaling and are competent to produce steroid hormones and to identify whether release is sound evoked; and 2) test the ability of selective activation of the cochlear CRF signaling system in protecting against NIHL. Data from this project will be important for writing a competitive R01 designed to examine the role of steroid release from specific cell populations.
Hearing loss afflicts 25-30 million people in the US, and much of it is due to excessive noise exposure. Significant economic impacts are related to noise-induced hearing loss, including $1.1 billion paid in 2005 to veterans with service-related noise-induced hearing loss. We will explore a newly discovered biological system that protects the inner ear against noise-induced damage with the expectation that a more complete knowledge of this system may reveal new drug targets for future therapeutic treatments against cochlear injury.
| Lykhmus, Olena; Voytenko, Larysa P; Lips, Katrin S et al. (2017) Nicotinic Acetylcholine Receptor ?9 and ?10 Subunits Are Expressed in the Brain of Mice. Front Cell Neurosci 11:282 |
| Romero, Haylie K; Christensen, Sean B; Di Cesare Mannelli, Lorenzo et al. (2017) Inhibition of ?9?10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc Natl Acad Sci U S A 114:E1825-E1832 |
| Vetter, Douglas E; Basappa, Johnvesly (2016) Multiplexed Isobaric Tagging Protocols for Quantitative Mass Spectrometry Approaches to Auditory Research. Methods Mol Biol 1427:109-33 |
| Vetter, Douglas E (2015) The mammalian olivocochlear system--a legacy of non-cerebellar research in the Mugnaini lab. Cerebellum 14:557-69 |
