DRF is proud to support 23 highly qualified research scientists as they do groundbreaking research in the following areas:
Fundamental auditory research – development, genetics, molecular biology, physiology, anatomy and animal models
Hearing and balance restoration for infants, children and adults (cochlear implants, surgical therapy for otosclerosis, hair cell regeneration, hearing aids, medical therapy)
Hearing loss – aging, noise-induced, otosclerosis, viral infection (sudden deafness), ototoxicity, temporal bone pathology, otitis media, cholesteatoma and tumors
Vestibular and balance disorders (dizziness and vertigo, Meniere’s disease)
Tinnitus (ringing in the ears) and hyperacusis (decreased tolerance of sound).
DRF is committed to funding hearing and balance research at the level of a government grant. Throughout our 49-year history, DRF has awarded over $23 million through nearly 2,100 research grants to researchers who are dedicated to exploring new avenues of hearing science. This seed money has led to dramatic innovations that promise to increase options for those living with hearing loss, as well as protect those at risk. These innovations include the diagnosis and treatment of otitis media (middle ear infections), the cochlear implant, implantable hearing aids, breakthroughs in molecular biology and hair cell regeneration.
For this year’s grant selection, DRF’s Council of Scientific Trustees reviewed grant applications from renowned scientists at top research institutions around the United States. The research projects of 23 talented doctors were selected. Each will receive a grant of $20,000. DRF continues to live up to its well-established reputation as the leading source of private funding for research in hearing and balance science in the U.S.
Tamara Alliston, Ph.D., University of California at San Francisco
The Role of Cochlear Capsule Bone Remodeling in Hearing Loss
Although several bone diseases cause sensorineural hearing loss, the mechanism by which bony defects impair auditory function remains unclear. The long-term goal of this research is to better understand the role of bone in the sensorineural function of the ear – with the objective of identifying bone targets that might be therapeutically effective in the prevention or reversal of hearing loss. The goal of this proposal is to test the hypothesis that abnormal remodeling of the cochlear capsule results in hearing loss by damaging the material quality of the cochlear bone matrix. Our recent studies on bone disease-associated hearing loss have shown that cochlear bone hardness is critical for hearing. Understanding bisphosphonate action in the ear is clinically important because drugs are commonly used to treat osteoporosis and bone disease-associated hearing loss.
Dwight E. Bergles, Ph.D.,
Johns Hopkins University
Connexin Involvement in Spontaneous Activity in the Developing Cochlea
Our recent studies indicate that spontaneous activity in the developing auditory nerve is initiated by the release of ATP from supporting cells in the organ of Corti. The goal of these studies is to evaluate the role of connexins in triggering ATP release from supporting cells. We propose to use electrophysiological and imaging methods in whole-mount preparations of pre-hearing cochleas to probe the sensitivity of spontaneous activity to manipulations that inhibit gap junction/hemichannel activity. We will extend these studies by testing whether expression of connexin 26 mutants associated with congenital hearing loss (R75W, W44C) alters this spontaneous activity. The studies outlined in this proposal seek to test the hypothesis that connexins play an essential role in the propagation of Ca2+ waves through the support cell network, and are responsible for the release of ATP in the developing organ of Corti.
Takako Kondo, Ph.D.,
Indiana University School of Medicine
Role of T1x3 Signaling in Inner Ear Sensory Neuron Development
The primary goal of this study is to elucidate novel functions of the Y1x3-class homeobox gene 3 (T1x3) in the development of inner ear sensory neurons. The specific aims in this study are to test whether T1x3 is required for normal development of inner ear sensory neurons, and to test whether T1x3 is sufficient for multipotent progenitor cells in the early embryonic ear to become competent to commit to a glutamatergic neural subtype. The long-term goal of this study is to clearly understand the molecular mechanisms underlying specification of auditory and vestibular neurons.
Patricia A. Loomis, Ph.D.,
Rosalind Franklin University of Medicine and Science
Splicing Regulation of Pre-mRNA Generated from the Deafness-Associated Espin Gene
The goal of this proposal is to determine how Espin gene expression is controlled at the level of RNA processing. Loss of function mutational analysis will identify RNA sequences on the Espin pre-mRNA that are essential for alternative splicing reactions. Proteins that bind the regulatory RNA sequences will be identified by UV-cross-linking, Western blotting and immunoprecipitation. Correlation of the in vitro analysis with in vivo activity will be accomplished through modulating by RNAi and overexpression of the levels of these proteins in HeLa cells transfected with Espin mini-gene constructs containing genomic sequence corresponding to the alternatively spliced exon and flanking introns.
Ania Majewska, Ph.D.,
University of Rochester
Cortical Synaptic Plasticity in a Mouse Model of Moderate Sensorineural Hearing Loss
The development of cortical networks is exquisitely sensitive to patterned activity elicited through sensory stimulation. Although much is known about somatosensory and visual cortical development, very little is known about the development of auditory cortex network connectivity. Changes in hearing that occur as a result of defects in sensation at the cochlea likely affect the development of higher brain areas which process auditory information. Our research will explore changes in the neural networks that process auditory stimuli in the cortex in a mouse model where prestin, a protein crucial for outer hair cell electromotile function, is absent during development. We will address this question by looking at synaptic sites which link individual neurons into networks and compare their density, distribution and dynamic remodeling in control and prestin-null mice. We hypothesize that changes in both static and dynamic synaptic structure will be present in the auditory cortex of prestin-null mice, suggesting that cortical auditory networks are altered by degraded hearing during development. This work will shed light on synaptic mechanisms and possible treatments of developmentally acquired hearing loss.
Mirna Mustapha-Chaib, Ph.D., University of Michigan
The Functional Role of the Unique Amino Terminus of Myo15 in Hearing Using Genetically Engineered Mice
Assessing the role of the N-terminus of MYO15 in structural development of hair cells and in the neurosensory process of hearing is expected to provide basic information about the process of hearing at the molecular level. Long term, we expect proteins that interact with the N-terminus of MYO15 will also be defective in some forms of hearing loss. Models similar to the one we propose have been used as proof of principle for gene therapy. Mutations in humans indicate that the N-terminal portion of MYO15 is required in some way for hearing. Using our resources and experience in genetically engineered mice will advance the understanding of the specific molecular function of the N-terminus of Myo15 in mammalian hearing and determine the consequences on morphological development and signal transduction within the cochlear hair cells. Thus, these studies will immediately make a contribution to the rapidly advancing field of molecular hearing research. The next step will be to identify the proteins that interact with the N-terminus, screen pedigrees for mutations in these genes and work towards therapeutic intervention for genes that are common causes of deafness.
Tatjana Piotrowski, Ph.D.,
University of Utah Medical School
Molecular Analysis of Hair Cell Regeneration in the Zebrafish Lateral Line
We are aiming to elucidate the genetic pathways underlying hair cell regeneration in zebrafish with the long-term goal of activating these pathways in mammals. Our lab is taking a two-fold approach to identify genes involved in hair cell regeneration. We are performing gene expression analyses from mantle cells of control larvae and from larvae in which mantle cells are proliferating to regenerate killed hair cells (as proposed in this application). As a second approach we are performing a mutagenesis screen for zebrafish mutants which are not able to regenerate hair cells, and thus carry mutations in regeneration-specific genes. A prominent cause of deafness is loss of hair cells due to age, noise or antibiotic treatments. In contrast to mammalian hair cells, fish, bird and amphibian hair cells turn over frequently and regenerate following hair cell death. Little is known why lower vertebrates are able to regenerate hair cells but humans cannot. This is partly due to the relative inaccessibility of inner ear hair cells to direct observation and manipulation. Our aim is to take advantage of the lateral line of zebrafish to define and characterize the molecular and cellular interactions occurring during hair cell regeneration. If successful, our results will set the stage for testing whether hair cell regeneration can be activated in humans.
Sonja Pyott, Ph.D., University of North Carolina Wilmington
Enhancement of the Efferent-Hair Cell Synapse by Metabotropic Glutamate Receptors
This proposal aims to improve our understanding of the molecular mechanisms regulating synapses in the cochlea and will specifically characterize how a class of molecules, metabotropic glutamate receptors (mGluRs), regulates the efferent-hair cell synapses. Sensory hair cells of the cochlea communicate with the brain at specialized sites called synapses. Inner hair cells have numerous afferent synapses that relay information about sound from the hair cell to the brain. In contrast, outer hair cells are characterized by efferent synapses from the brain that regulate hair cell activity. Although these efferent and afferent synapses are normally considered to be independent from one another, experiments studying immature inner hair cells suggest that glutamate, the neurotransmitter required for transmission at the afferent synapse, may also modify the response of the efferent synapse. Efferent innervation of the cochlea is thought to protect against noise-induced hearing loss. Considering that noise-induced hearing loss accounts for one-third of all cases of deafness, understanding the mechanisms regulating efferent synapses is of special clinical relevance. This project will investigate this hypothesis and should uncover novel pharmaceutical targets to modulate the efferent synaptic response to either dampen hair cell activity and prevent noise-induced hearing or boost hair cell activity and combat deafness.
Robert M. Raphael, Ph.D.,
Rice University
Single Molecule Investigation of the Effects of Oxidative Stress on Prestin Oligomerization and Prestin-Cytoskeletal Interactions
Modern medicine is currently powerless to cure those affected with this sensorineural hearing loss due to our very limited understanding of underlying molecular mechanisms. The long-term objective of this research is to deepen our understanding of prestin-prestin and prestin-cytoskeleton interactions and determine whether these interactions are perturbed by oxidative stress. To achieve this goal, we will utilize single molecule fluorescence imaging, a powerful technique for studying the molecular interactions of membrane proteins. Our sense of hearing depends on cells inside the cochlea that amplify the motion of vibrating structures of the inner ear. These cells are called outer hair cells (OHCs) and supply energy to the cochlea by a voltage-induced length change referred to as electromotility. A protein called prestin that resides within the membrane of OHCs is responsible for electromotility. The ability of prestin to transmit force from the membrane to the underlying cytoskeleton depends on how the membrane is organized. Up to now, scientists have used conventional imaging techniques to visualize the structure of the OHC membrane. Recent advances in high resolution optical imaging have made it possible to study the fluorescence signals from single molecules in cells and thus study the organization of cell membranes at the molecular scale. In this proposal, we plan to apply this exciting new technology to study the molecular interactions of prestin for the first time. The research in this proposal will test the specific hypothesis that ROS disrupts the intermolecular interactions and membrane organization of prestin. If this hypothesis is proven true, it would suggest specific pharmacological interventions to prevent or alleviate noise-induced hearing loss and presbycusis and potentially restore normal auditory function.
Valeriy Shafiro, Ph.D.,
Rush University Medical Center
Perception of Environmental Sounds and Speech in Patients with Cochlear Implants
This project will assess the ability of patients with contemporary cochlear implants to perceive environmental sounds using a new test of environmental sound perception. It will further examine the relationships between perception of environmental sounds and speech. A close association between these abilities would open an exciting possibility of developing a language-independent instrument for estimating speech perception abilities based on environmental sound tests (e.g., when speech materials are not available for some languages for potential candidates). Such a test would have highly useful clinical applications in large urban clinics or in developing countries with fledgling implant programs.
Lisa D. Urness, Ph.D.,
University of Utah
FGF-Regulated Hearing Loss Genes: Fast-tracking to Functional Analysis
With the myriad roles of fibroblast growth factors (FGFs) in multiple stages of ear development, it is not surprising that some human hearing loss syndromes are caused by mutations affecting FGFs and their receptors. However, little is known about the genes that are controlled by FGFs. Because FGF signals are reused during later stages of otic innervation, morphogenesis and sensory cell differentiation, the FGF target genes we identify during placodogenesis may also be targets of later FGF signaling events and could provide many new candidates for hearing and/or balance disorders, thereby impacting diagnosis. Importantly, elucidating the functions of these genes may suggest potential therapeutic interventions. Fibroblast growth factors are required to initiate otic development and are subsequently reused during morphogenesis and sensory development. Our long-term objective is to identify FGF effector genes and to determine their function and relevance to human deafness by analyzing mouse mutants. Specifically, we propose to isolate RNA from pre-otic ectoderm of control and FGF-deficient embryos and perform an expression profiling experiment utilizing a “gene-trap microarray.” This will identify embryonic stem cell lines that carry mutations in FGF target genes. Selected cell lines will be used to generate the corresponding mutant mouse strains for functional studies of hearing and balance.
Ilse Wambacq, Ph.D.,
Montclair State University
Neurophysiological and Psychoacoustic Indices of Binaural Processing in Adults
The overall goal of the proposed research is to investigate neurophysiological and psychoacoustic indices of binaural processing in adults with normal and impaired hearing. In order to develop and implement effective remediation for individuals with sensorineural hearing loss, it is essential to determine a straightforward means to identify binaural processing problems. It is particularly important to ascertain the relationship between neurophysiological and psychoacoustic measures because there are many individuals for whom it is difficult to obtain behavioral responses. In the proposed study we will evaluate the effect of sensorineural hearing loss on processing of IIDs and determine the relationship between neurophysiological and behavioral measures of sensitivity to IIDs. Results will provide the information necessary to assess binaural processing of IIDs and to develop remediation strategies for individuals with sensorineural hearing loss.
Julian R. A. Wooltorton, Ph.D., University of Pennsylvania
Probing the Inner Hair Cell Bundle Displacement-quantal Synaptic Response Transfer Function
How do sub-micron displacements of hair bundles on inner hair cells lead to a neural code perceived as sound? This proposal investigates the critical relationship (or transfer function) between hair bundle displacements and afferent fiber bouton responses in the gerbil cochlea. Understanding how we encode the acoustic wave into sound is vital to hearing research. By investigating the relationship between the response to acoustic waves of sensory cells in the cochlea and the resulting postsynaptic neuronal response, we will provide vital information on how the first synapse in the auditory pathway works. This is the basic step carried out by cochlear prostheses. Further insight into the biological details of this encoding step promises new information on how to improve the design and performance of cochlear prostheses and help to further ameliorate hearing loss and deafness. Mechanical energy of an acoustic wave enters the ear en route to the cochlea where it is translated into the electrical signals of the auditory nerve. This process involves numerous steps dependent upon the unique architecture of the mammalian ear and various specialized cellular processes to maintain fidelity in reporting frequency, amplitude, timing and range of auditory stimuli. The inner hair cell processes acoustic waves in the cochlea. A hair bundle atop this cell senses acoustic stimulus and allows current to flow into the hair cell. This ultimately results in neurotransmitter release onto an afferent fiber bouton and subsequent sound perception. One of the true wonders of the biological world is the ability of the auditory system to detect the nearly molecular scale displacements of the hair bundle that result from acoustic wave stimulation. How these tiny displacements lead to a neural code that we perceive as sound is poorly understood. In this application, we propose to define the quantitative relationship (transfer function) between inner hair cell bundle displacement and the quantal response in the afferent fiber bouton.
Donate Now!
DRF funds research that changes lives.
