University of California San Diego

Canonical wnt signaling in the developing organ of corti

Within the organ of Corti, a single row of inner hair cells and three rows of outer hair cells extend along the basal- to-apical axis of the cochlea. Every sensory hair cell is separated from the next by an intervening non- sensory supporting cell, resulting in an invariant and alternating mosaic. The importance of the formation of this structure is illustrated by the significant auditory deficits in animals with patterning defects in the cochlear duct. Since the perception of sound is based on the integrity and function of this strict cellular organization, it is important to elucidate the developmental processes responsible for generating and regulating this pattern. The development of the cochlea and the organ of Corti requires several events including growth, specification of cell fates, proliferation and differentiation. In many systems the Wnt/_-catenin pathway plays a crucial role in determining cell fate, growth and proliferation. We have data indicating that several Wnt signaling genes are expressed in the cochlea. Furthermore, our preliminary results demonstrate that activating the Wnt/_-catenin pathway in whole organ cochlear explant cultures results in a robust increase in the size of the prosensory domain that gives rise to the organ of Corti and increases in auditory hair cells.

Medical University of South Carolina

Neural changes underlying speech-perception training in the aging brain

Many older adults with hearing loss have difficulty understanding speech in noisy environments and some feel socially isolated. Although hearing aids can improve speech understanding, hearing aid benefit may be limited if the perception of certain speech sounds has changed. Speech training programs have been shown to improve the recognition of amplified speech by older adults by focusing on re-learning cues important for perception of specific sounds. The goal of our study is to examine how the brain changes during speech training programs designed to improve speech understanding in noise. To achieve this goal, we are using MRI to examine brain activation before and after speech training and relate this activation to improvements in speech recognition. Our long term goal is to enhance the effectiveness of speech training programs by understanding the brain systems that are important for learning to hear amplified speech.

This research award is funded by the Centurions of the Deafness Research Foundation. DRF partnered with CORE Grants Program of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) to offer a one-year Centurion Clinical Research Award (CCRA) for clinical research in hearing and balance sciences.

Rosalind Franklin University of Medicine and Science

Therapeutic correction of Ush1c splicing in a mouse model of usher syndrome

Usher syndrome is the leading genetic cause of combined hearing and vision loss. The long-term objective of this project is to develop therapeutics for the disease. Antisense oligonucleotides (ASOs) will be used in a mouse model of Usher syndrome to correct a specific genetic defect that causes the disease. This work will demonstrate the efficacy of ASOs as a therapeutic for Usher syndrome and will also provide insights about curing the disease.

University of Maryland School of Medicine

A new protocol for selective and efficient sorting of the auditory sensory epithelium

The goal of this project is to develop methods for separating and characterizing the unique cell types of the auditory sensory epithelium using methods commonly used by immunologists. This could also result in the identification of new cell type-specific proteins and possibly new deafness genes.

Boston University School of Medicine

An active role for the supporting cell cytoskeleton in controlling hair cell death and regeneration

Cochlear hair cells are the primary targets of most damaging agents. When these cells are lost in humans and other mammals, the resultant hearing loss is permanent. However, chickens and other avian species have the ability to replace lost cochlear hair cells. Cochlear hair cell regeneration occurs through two different mechanisms: Direct transdifferentiation (DT) and mitotic proliferation. In DT, supporting cells directly alter their gene expression to become new hair cells. Alternatively, in mitotic proliferation, normally quiescent supporting cells are induced to proliferate and differentiate into new hair cells and new supporting cells following the death and ejection of the original sensory cells. The experiments in this research are designed to examine how supporting cells regulate hair cell death and how this subsequently regulates supporting cell proliferation. Additionally, we are trying to prevent both the death and ejection of cochlear hair cells. If cochlear hair cells can be “trapped” and “rescued” by treatment with various inhibitors, these compounds may be useful therapeutic tools in hearing loss prevention.

University of Chicago

Mitochondrial DNA deletions and cochlear element degeneration in presbycusis

The long term goal of the Bloom Temporal Bone Laboratory is to understand the molecular mechanisms involved in age-related hearing loss and develop a rationale for therapy based on this information. This project will quantify the mitochondrial DNA common deletion level and total deletion load in the cochlear elements obtained from individuals with presbycusis and normal hearing controls. The relationship between deletion levels, the extent of cochlear element degeneration, and the severity of hearing loss will be explored in human archival tissues to clarify the role of deletions in presbycusis.

This research award is funded by The Burch-Safford Foundation Inc.

University of Utah

The role of Fgf4 in otic placode induction

Development and patterning of the inner ear is a complex process that is mediated by several signaling molecules, including members of the fibroblast growth factor (FGF) family. We recently found that Fgf4 is expressed in the ear-forming region just prior to the induction of ear development. Fgf4 has not previously been described in the induction or formation of the inner ear. Based on its temporal and spatial pattern of expression we hypothesize that Fgf4 is involved in the early processes of ear development and propose to investigate its role(s) in these processes by determining whether it is sufficient and/or required to induce the early stages of inner ear development. We also will examine the signals responsible for localizing Fgf4 expression to the otic forming domain.

The City College of New York

Defining the role of olivo-cochlear feedback in the development of the auditory brainstem

During early brain development auditory neurons spontaneously generate highly patterned electrical activity in the absence of sound. In this project Rodriguez-Contreras will explore the role of cholinergic brainstem neurons in modulating the patterns of spontaneous activity. His work could provide clues to develop treatments that ameliorate hearing impairments such as tinnitus and deafness.

University of Washington

Assessing functional recovery after mechanosensory hair cell regeneration in the zebrafish lateral line

Sensory hair cells located in the inner ear are responsible for converting sound into understandable signals for the brain. Damage of these cells from age-related factors, noise, and therapeutic drugs leads to hair cells loss, a process that is irreversible in humans and other mammals. In contrast, non-mammalians, such as zebrafish, are very effective in regenerating sensory hair cells; therefore, we use this organism to find mechanisms that lead to sensory hair cell regeneration. Since restoration of function depends on restoring the correct connections between hair cells and the brain, I am using a behavioral assay and molecular markers to determine how this process is accomplished during regeneration.

New York University School of Medicine

Measuring and predicting the quality of nonlinearly distorted music and speech as perceived by hearing-impaired people

Hearing aids and other communication devices, such as telephones, introduce significant nonlinear distortion which reduces sound quality and may interfere with speech perception. The goals of the proposed research are to characterize and model the perception of distorted speech and music by hearing-impaired listeners. The first objective of the proposed research is to conduct listening tests to determine how hearing-impaired listeners evaluate the perceived quality of distorted speech and music. The second objective of the proposed research is to develop a computational model for predicting perceived quality judgments made by hearing- impaired listener; in other words, to predict the data obtained in the first part of the project. The third objective of the proposed research is to test, and if necessary to refine, the developed models using recordings of speech and music replayed via existing assistive hearing devices.

House Ear Institute

“Forkhead box o” transcription factors and mammalian cochlear regeneration

To restore hearing to the deaf will require an understanding of the genes that regulate proliferation of adult supporting cells. While tumor suppressors, such as Cdkn1b, have well described functions in the cochlea, upstream regulators of such genes are not understood. White’s research will characterize the expression and function of Foxo3 (Forkhead box O3), a candidate regulator of Cdkn1b, in supporting cells.

University of North Carolina at Chapel Hill

Synaptic transmission in the principal cells of the anteroventral cochlear nucleus during age-related hearing loss

Age-related hearing loss (AHL) is a common disorder that affects most individuals as they age and causes conditions from deteriorated hearing sensitivity to complete deafness. Anatomical and physiological changes in the auditory system during AHL underlie the perceptual loss of hearing. Changes in cochlear nucleus, which is the first processing center of the central auditory system, are of special interest in studying AHL. However, little is known about the changes of synaptic transmission in principal cells of the cochlear nucleus during AHL except a pioneering study from this lab. This project will utilize DBA/2j mice as the animal model for AHL to study the changes of synaptic transmission in principal cells of anteroventral cochlear nucleus (AVCN) during AHL. Specifically, the study will use whole-cell recording techniques to evaluate the glycinergic transmission in bushy cells as well as both glycinergic and glutamatergic transmission in stellate cells of the AVCN in brain slices prepared from DBA/2j mice at three age groups, which represent three different developmental stages of AHL (normal hearing, intermediate hearing loss, and complete hearing loss). The study seeks to identify physiological changes in synaptic transmission in the principal cells of AVCN during AHL that may underlie the perceptual loss of hearing.

Tufts University School of Medicine

The role of Neuregulin1 signaling in the developing cochlear nucleus

The long-term objective of this study is to understand the genetics of cochlear nucleus neuronal differentiation and specification to examine how information-transmitting cells in the brain (neurons) obtain their identity and acquire specific characteristics that endow them to perform very specific functions.

Johns Hopkins University School of Medicine

Dopaminergic modulation of inner hair cell afferent synaptic transmission

In the inner ear, the inner hair cells convert sound information into electrical signals. Auditory nerve fibers pick up information from the hair cells via the hair cell afferent synapse and transmit the sound signal to the brain. Interesting, auditory nerve fiber activity can be modulated by feedback mechanisms from the brain. Lateral efferent fibers originating in the auditory brainstem innervate auditory nerve fibers at their endings, directly where they contact the inner hair cells. Dopamine is one of the neurotransmitters found in lateral efferent endings and dopamine release is thought to provide a protective role against noise-trauma. However, the cellular mechanisms underlying this process are not well understood. In this project, we will use histological techniques to identify the cellular locations and subtypes of dopamine receptors at the inner hair cell afferent synapse. We will also use electrophysiological techniques to measure electrical impulses in auditory nerve fiber endings at the hair cell afferent synapse in an excised cochlear preparation. We will apply drugs that specifically imitate or inhibit the actions of dopamine, and investigate the mechanisms and intracellular targets by which dopamine receptors modulate the signals at the inner hair cell afferent synapse.