University of Michigan
Ototoxicity of a common drug delivery tool and FDA Orphan Drug, 2-hydroxypropyl-beta-cyclodextrin

Cyclodextrins are a class of molecules that can dissolve cholesterol and other lipids in the body. They are commonly found in household cleaning products, and they are being studied in the treatment of Niemann-Pick disease. Unfortunately, cyclodextrins cause hearing loss and damage to the cochlea at high doses. This project will study the effects of 2-hydroxypropyl-betacyclodextrin (HPBCD) on hearing in a mouse model by injecting this drug under the skin and into the brain. This research will quantify the level of hearing loss and cochlear damage caused by this medication. In addition, the mechanisms of hearing loss and ototoxicity through a variety of techniques will be studied. This novel approach to studying HPBCD may have powerful impacts for patients with Niemann-Pick disease as well as advance our understanding of drug related ototoxicity.

Research area: Hearing loss; Ototoxicity

Long term goal of research: To develop novel tools for both the prevention and treatment of hearing loss. Cyclodextrins are powerful drugs that can be used to deliver a variety of drugs into the eye, brain, and even the ear. They can also be used to treat lysosomal storage disorders such as Niemann-Pick disease. Unfortunately, at high doses they cause hearing loss and damage the cochlea. The long-term objective is to understand the mechanisms of cyclodextrin induced hearing loss. Hopefully this will lead to novel strategies to ameliorate cyclodextrin damage while retaining its drug-delivery and therapeutic advantages. In addition, new therapeutic uses for HPBCD to treat inner ear disorders will be developed.

University of Minnesota
Behavioral and neural correlates of amplification outcome

Understanding individual factors, beyond hearing thresholds, that account for the high variability in success in the use of hearing aids is an important question with immediate clinical implications. This project aims to evaluate how fundamental aspects of auditory processing interact with high-intensity sounds and influence hearing aid amplification outcomes. Behavioral and speech and non-speech measures will be used to determine how spectral auditory processing interacts with high intensity sounds and influences amplification. This will help us determine factors that contribute to diminished speech perception in noisy environments for individuals with hearing loss and how their perception of amplified speech can be enhanced in noisy environments.

University of Southern California
Filtering of otoacoustic emissions: a window onto cochlear frequency tuning

Healthy ears emit sounds that can be measured in the ear canal with a sensitive microphone. These otoacoustic emissions (OAEs) offer a noninvasive window onto the mechanical processes within the cochlea that confer typical hearing, and are commonly measured in the clinic to detect hearing loss. Nevertheless, their interpretation remains limited by uncertainties regarding how they are generated within the cochlea and how they propagate out of it. Through experiments in mice, this project will test theoretical relationships that suggest that OAEs are strongly shaped (or “filtered”) as they travel through the cochlea, and that this filtering is related to how well the ear can discriminate sounds at different frequencies. This may lead to novel, noninvasive tests of human cochlear function, and specifically frequency discrimination, which is important for understanding speech.

Harvard University
Identifying roles for contact-dependent signaling between neurons and glia during axon guidance and synaptic targeting

The mature cochlea is a spiraled hollow chamber of bone that contains all the necessary components to transmit sound information to the brain. This feat is accomplished by the precise arrangement of hair cells and spiral ganglion neurons (SGNs). This arrangement requires SGNs extend peripheral projections and establish precise synaptic connections with hair cells. What signals guide these axons through the three-dimensional terrain of the cochlea? Most studies focus on the roles of classically described axon guidance cues, which act over long distances to attract or repel axons. However, mounting evidence from recent studies and our own preliminary data lead us to hypothesize that contact-dependent signaling between SGNs and Schwann cells (SCs) are required for normal development of inner ear neural architecture and hearing. The precise role of contact-dependent interactions between SGN axons and SCs on auditory circuit formation remains unknown. This is due in part to the obstacles towards gathering high-resolution, time-lapsed information on the spatial relationships between SGNs and SCs in situ. Therefore, we will genetically label and characterize live cellular interactions between these cells in their normal, and then abnormal, physiological environment. We will measure the extent to which each of these cell types rely on each other for normal migration, differentiation, proliferation and survival. Because we have identified a mutant in which SGN-Schwann cell interaction appears disrupted, these studies will also provide insight to our understanding of Schwannoma formation. Schwannomas are Schwann cell tumors commonly found in the inner-ear and are thought to arise from a disruption in reciprocal signaling between spiral ganglion neurons (SGNs) and Schwann cells. As these tumors grow they compress afferent vestibular and auditory nerves, usually causing hearing loss, tinnitus, and dizziness. Therefore, these studies will not only contribute to our understanding of auditory circuit formation but also provide insight into what can go wrong when SGN-Schwann cell interaction is disrupted.

University of Cincinnati
Specifying the Integrity of Neurons in the Auditory Periphery (SiNAP)

Auditory nerve degeneration is thought to lead to difficulties with understanding speech, especially in noisy listening situations. Diagnosis of auditory nerve degeneration, however, may be missed by common hearing tests. This research examines the utility of a new technique to specify the extent and region of auditory nerve damage within the inner ear. Application of the technique in a clinical setting may help individualize hearing aids and cochlear implants, and in the future, guide delivery of therapeutic agents that can truly restore hearing to individuals with hearing loss.

Research area: Auditory physiology; Diagnostic audiology

Long-term goal of research: To develop tools for diagnosis of auditory nerve integrity that will improve the individualization of treatment options for individuals with hearing loss.

New York University School of Medicine
Neural computations for vestibular control of movement initiation

Loss of balance and falls are common in aging populations and associated with various neurological disorders. Balance is sensed using vestibular organs in the inner ear and processed in the brainstem. However, it remains unclear how the brainstem transforms sensations of instability into corrective movements that restore balance. The objective of this project is to define how cells in the brainstem act collectively to produce rapid responses to sensations of instability. In order to measure balance responses in populations of cells located deep within the brain, this project will apply cutting-edge microscopy techniques to the zebrafish. These fish swim to remain balanced, providing a model for balance control and brainstem function in general.

Baylor College of Medicine
Development of Biomarkers to Study Strial Development and Degeneration

The sensory hair cells of the cochlea are able to detect sound vibrations. Hair cells need a source of potassium that helps them to convert sound energy into electrical energy that is sent to the brain. Hair cells in our cochlea are bathed in a potassium-rich fluid called endolymph, and the potassium is constantly pumped into the endolymph by a specialized group of cells in the cochlea called the stria vascularis. As humans get older, the stria vascularis can degenerate, and so the “battery” that supplies potassium to the cochlea runs down, and we lose our hearing. The goal of this project is to understand how the stria vascularis develops, and to devise ways of looking at changes in this structure with age.

Research areas: the development and regeneration of the inner ear, stria vascularis development

Long-term goal of research: We hope this knowledge may allow us to repair or slow down damage to the cochlea and lessen the effects of age-dependent hearing loss.

Washington University
Role of FGF's in Cochlear Sensory Epithelium

Congenital sensorineural hearing loss is one of the most common hereditary disabilities, affecting 1 in 1000 children. Fgf20 null mice have congenital hearing loss associated with loss of sensory cells, and inactivation of both Fgf9 and Fgf20 result in a shortened cochlea. The goal of our research is to understand the cellular and molecular functions of Fgf9 and Fgf20 in inner ear development in vivo. The ultimate goal of this research is to learn how to direct the regeneration of malformed or damaged sensory tissue to restore or improve hearing.

Research area: hair cell regeneration

Long-term goal of research: My long term goal is to understand how Fgf signaling regulates the development, maintenance and repair of sensory hair cells and supporting cells in the cochlea. Due to lack of regenerative ability in humans after loss or dammage of hair cells, it is critical to identify signals that can reactivate developmental pathways and thus permit repair and regeneration of the damaged cochlea. Studying the mechanisms that regulate cochlear development will provide valuable clues about molecules that can be tested for regenerative activity and will thus benefit future translational studies aimed at inducing hair cell regeneration in adult humans.

University of Michigan
Investigating the role of Chd7 during noise-induced hearing loss

Mice born with loss of Chd7, the gene mutated in human CHARGE syndrome, exhibity middle ear defects and resistance to acoustic trauma. Preliminary results show that deletion of Chd7 in adult mice (using tamoxifen inducible Cre line) also results in variable resistance to acoustic trauma, even in the absence of middle ear defects. This suggests important functions for Chd7 in regulating hair cells and neuronal integrity in adult cochlea. The objective of this research is to identify how loss of Chd7 influences susceptibility to acoustic trauma in the mature cochlea.

Research area: noise-induced hearing loss (NIHL)

Long-term goal of research: to help identify novel genes and molecular pathways involved in protection from NIHL and provide rationale for designing new therapies.

University of Iowa
Misexpression of Neurog1 combined with delayed deletion of Atoh1 provides a novel model

Contemporary research is focusing on the regeneration of hair cells in hearing loss using Atoh1. Reconstitution of the organ of Corti requires proper organization of the two types of hair cells, inner and outer hair cells, as well as supporting cells. Recent data showed that level of Atoh1 determines the degree of survival of different types of hair cells. Jahan’s previous work demonstrated the survival of some organ of Corti-like cells without Atoh1 if replaced by a closely related transcription factor, Neurog1. It is now Jahan’s intent to investigate the effect of Atoh1 substitution with Neurog1 combined with a delayed loss of Atoh1 expression in viable animals. This combined mutant offers for the first time a critical test of presumed causalities of molecular mechanism that may regulate the patterning of the organ of Corti, including hair cell and supporting cell differentiation.

Research area: Hair Cell Regeneration

Long-term goal of research: To define the correct dose and duration of Atoh1 expression for type-specific hair cell development which will provide novel insights into hair cell regeneration.