Friday, April 4, 2025
4/4/2025
Calcium regulation and outer hair cell sensitivity to cochlear injury - PROJECT SUMMARY/ABSTRACT Acquired sensorineural hearing loss (SNHL) reflects a complex interaction between genetic, biochemical and environmental factors. The most common causes of acquired SNHL are cochlear injury from noise, aging and infection. Hallmarks of acquired SNHL are loss of outer hair cells (OHCs) and loss of afferent synapses below the inner hair cells (IHCs). Both OHCs and afferent synapses act as sentinels of cochlear injury. Comparatively little is known about the endogenous mechanisms necessary to protect OHCs from the damaging effects of cochlear injury and whether OHCs use a single mechanism in response to different types of cochlear injury. The long-term objective of this research is to develop effective treatments that ameliorate the effects of cochlear injury. This proposal focuses on the role of Ca2+ signaling in OHCs in mitigating responses to cochlear injury. Our overall hypothesis is that calcium regulation in OHCs mediates the sensitivity of the cochlea to injury, which determines the extent of hair cell loss and hearing loss. Specifically, we hypothesize that inner ears lacking oncomodulin (OCM) will demonstrate higher threshold shifts, purinergic signaling and inflammatory responses to cochlear injury. We will use in vivo functional assays assessing cochlear thresholds, mRNA and protein assays, and confocal and electron microscopy in Ocm mutant and wild-type (WT) mice. Specific Aim 1 investigates OHC Ca2+-dependent functional sensitivity to cochlear injury. We hypothesize that Ocm deletion increases vulnerability to noise and is associated with higher levels of Ca2+ signaling in OHCs. Thus, in the absence of Ca2+ buffering, OHCs become more sensitive to trauma resulting in higher hearing thresholds independent of the traumatizing stimulus. We will use noise and LPS treatments to test whether any increased sensitivity of OHCs to cochlear injury uses a common, Ca2+ depending pathway. Specific Aim 2 investigates purinergic receptor signaling mediation of OCM deficiency following cochlear injury. We hypothesize that a lack of Ca2+ buffering through OCM triggers increased purinergic receptor expression leading to exaggerated Ca2+ responses in OHCs. Chronic abnormal Ca2+ signaling may increase purinergic signaling and thus, prime OHCs in such a way as to have increased or exaggerated responses to low-level damaging stimuli that lead to increased hearing thresholds. Specific Aim 3 investigates Ca2+-dependent survival following cochlear injury. We hypothesize that a lack of Ca2+ buffering through OCM negatively impacts OHC survival, triggering programmed cell death and up regulating pro-inflammatory pathways. If noise and LPS produce similar changes, it further supports, not only that Ca2+ regulation is critical for OHC sensitivity to injury, but also that Ca2+ regulation in OHCs is linked to pathogen recognition receptor pathways. Thus, cochlear injury should lead to a greater loss of OHCs in Ocm mutants. In summary, these studies should enhance our understanding of the role of Ca2+ regulation in protecting auditory function. Undergraduates will play significant roles in the collection and analysis of data of each aim.
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