These researchers received grant funding from the American Hearing Research Foundation in 2018. Click to read about their studies.
Jessy Alexander, PhD
Department of Medicine
State University of New York at Buffalo
Complement, hearing loss and lupus
Summary: Lupus: the disease landscape. Systemic lupus erythematosus (SLE), commonly known as lupus affects 13–39.0 per 100,000 people. Women are 9 times more likely to be affected than men. Lupus affects different organs including the auditory system. Hearing loss typically occurs between 15-45 years of age and lowers the quality of life. The current treatments for lupus-related hearing loss is corticosteroid treatment, which has toxic side effects. Therefore, there is an urgent new develop new biomarkers and therapeutic treatments. (Read more)
Complement system: Traditional and expanded functions. The complement system, a complex of more than 30 proteins, is an important arm of the body’s defense that helps eliminate infectious microorganisms. The complement system is strictly regulated to prevent host tissue injury and inflammation. New research shows that complement proteins participate in precise brain development. Further, it efficiently recognizes and controls elimination of damaged cells thereby preventing inflammation and ensuing autoimmune tissue damage. Recent studies indicate that complement proteins are associated with hearing loss due to ear infections and lupus.
Drive to find new therapeutic targets. New drugs that inhibit the complement system have advanced to clinical trials for the treatment of age-related macular degeneration while other FDA-approved drugs are currently marketed as a therapy for paroxysmal nocturnal hemoglobinuria, and is now in pre-clinical trials for other complement disorders. More promising therapies that suppress the complement system include small molecules that inhibit C3 cleavage and C5a receptor antagonists. Because the complement system is also necessary to maintain health, it is necessary to identify complement products in each setting that could serve as effective therapeutic targets. In line with this need, this proposal will attempt to understand the role of the complement system and associated changes in hearing loss in a setting where complement activation occurs.
The laboratories involved. The laboratory of Jessy Alexander, a complement and lupus expert will join hands with the laboratory of Richard Salvi, an expert in hearing, to study the role of the complement system in lupus-related hearing loss with the goal of identifying potential therapeutic targets that can alleviate the hearing loss in lupus patients. This is important since, identifying complement targets and optimizing their delivery to the organs of interest in particular clinical settings have important clinical translational significance.
Karl Doerfer, MD
Resident – PGY-4
Department of Otolaryngology & Communication Sciences
Medical College of Wisconsin Affiliated Hospitals, Milwaukee
Christina Runge, PhD
Chief, Division of Communication Sciences
Medical College of Wisconsin, Milwaukee
Bernard and Lottie Drazin Memorial Grant for Residents: $1,000
Development of In-House Genetic Screening for Pediatric Hearing Loss
Summary: Approximately 1-2 out of every 1,000 children are born with hearing loss, and genetic factors are responsible in approximately 50% of cases. Research also shows that children who are born with normal hearing can inherit genes that place them at risk for hearing loss as they get older. For example, some genes increase risk for hearing loss from head trauma, some from specific medications and others from certain environmental exposures.
Nearly all infants are screened for hearing loss within the first month of life. Screening allows health care providers to confirm hearing loss with additional diagnostic testing and to intervene when appropriate with treatments, such as hearing aids and cochlear implants. However, screening and diagnostic tests may miss children with mild forms of hearing loss, and they do not provide information about the underlying causes for a patient’s hearing loss. They also cannot identify children with normal hearing who inherit genes that put them at risk for hearing loss as they get older.
Genetic testing is beginning to change this. Using genetic analysis, we can often identify which genes are responsible for hearing loss. We can also identify some children who are at risk for losing hearing as they age. When health care providers understand the genetic mechanism for a patient’s hearing loss, they can provide better counseling and guidance to a child’s parents about treatment options, prognosis, and avoiding risk factors that may increase hearing loss over time.
While genetic testing is very promising and increasingly affordable, it can be very time consuming. Currently, it can take several months to obtain results. In order to address this problem, Children’s Hospital of Wisconsin, in partnership with the American Hearing Research Foundation, developed an in-house protocol to perform genetic testing for hearing loss. Our goal is to provide a model that other medical centers can use to optimize such testing. When we analyzed our data, we found that we were able to reduce turnaround times from an average of 54 days to 19 days. We also found that certain hearing test results were associated with increased rates of positive genetic testing. These findings are relevant to medical centers who hope to expand the role of genetic testing for pediatric hearing loss: They demonstrate that genetic testing can be done quickly, reducing delays in diagnosis and expediting treatment. They also show that certain simple hearing tests can help identify children who are likely to benefit from genetic testing. We are hopeful that our efforts can help expand the role of genetic testing for pediatric hearing loss and improve care for this patient population.
Michael M. Ebeid, MBBCh, PhD
Post-doctoral Research Associate
Department of Developmental Neuroscience
Munroe Meyer Institute for Genetics and Rehabilitation
University of Nebraska Medical Center, Omaha
Mechanism of FGF signaling in regulating mouse cochlear progenitor proliferation
Summary:The inner ear is responsible for hearing and balance. It contains a spiral-shaped structure called the cochlea that includes sensory cells (also called hair cells) responsible for converting sound waves to electrical signals. These cells are vulnerable to damage due to loud noise, aging or some medications. Once damaged, hair cells are not replaced causing permanent hearing loss. Current research efforts aim at developing strategies to protect or replace damaged hair cells. Studying development can provide important clues for regeneration. In embryo, hair cells develop from precursor cells called progenitors, (Read more) and the ultimate length of the cochlea is determined by the number of these progenitors. In previous study, our lab showed that two proteins called FGF9 and FGF20 work together to regulate the number of progenitor cells and thereby the cochlear length. These proteins are produced at an early stage of development and signal to specific cells containing receptors that are activated by these proteins.
Our current research aims at exploring the mechanisms by which these 2 proteins (FGF9 and FGF20) regulate sensory progenitor development. We are using mouse models carrying mutations within these 2 proteins or their receptors to investigate the downstream effects of such mutations on the development of cochlea. Our goal is to understand the mechanism by which sensory progenitors develop and expand during development then utilize such knowledge to develop new strategies to repair or replace sensory hair cells.
(Right: Pictured with Spanish colleagues Carmen Martin-Sierra, Theresa Requena, Jose Antonio Lopez-Escamez)
Anna Lysakowski, PhD
Department of Anatomy & Cell Biology
College of Medicine
University of Illinois at Chicago
Understanding genetic heterogeneity in familial Meniere’s Disease
Summary: Ménière’s Disease (MD) is a complex disorder of the inner ear characterized by episodes of vertigo, fluctuating and progressive low to middle frequency sensorineural hearing loss and roaring tinnitus — symptoms that often lead to chronic dizziness. It afflicts as many as 1 in 1000 Americans and it has a strong genetic predisposition with a familial clustering in 9% of cases in populations of European descent. Although a subset of MD patients may respond to immuno-suppressants and corticosteroids, the majority of patients progress to severe deafness in the involved ear. Bilateral MD has a highly significant impact on quality of life and may be involved in up to 40% of MD patients.
Human inner ear tissue is difficult to obtain, so progress towards a directed treatment will depend upon genomics-based approaches to identify the genes and pathways involved in MD patients and the development of cellular and animal models to increase the understanding of MD. Recently, we identified and validated five novel mutations in familial MD by whole exome sequencing, but their roles in hearing and balance are unknown. The purpose of this small grant proposal is to generate preliminary data for a full-size NIH grant.
The current proposal, to be undertaken at UIC in Chicago, will focus on two of three aims. Aim 1 is to localize, at both the confocal and ultrastructural levels, the proteins encoded by these genes in the mouse cochlea and vestibular system with immunohistochemistry using fluorescent confocal microscopy and immunogold EM. Aim 2 is to validate the antibodies used Aim 1 in knockout mice specific to those gene products with the eventual goal of establishing a mouse model for each target protein. Aim 3, a future direction, is to generate human cellular models of MD using patient-derived induced pluripotent stem cells (iPSCs). Aim 3 will be done in collaboration with our colleagues in Spain, who have gathered the preliminary data related to this project from a large population of MD patients.
In summary, we expect to identify crucial genes and cells involved in familial MD to generate the first human cellular models of MD. The combined structural, stem cell-based, and gene therapy approaches of the entire project will significantly impact the development of therapies for MD. The structural studies proposed in this application are fundamental for determining the localization of genes identified by the other approaches.
Determination of the Auditory Function of the Outer Hair Cell Afferent Synapses in the Mammalian Cochlea
Summary: This project aims to better understand our sense of hearing, which allows us to communicate with each other by receiving sounds and interpreting speech. Within the inner ear is a structure called the cochlea, which contains two types of cells: inner hair cells (IHCs) and outer hair cells (OHCs). These cells are specialized sensory cells that have tufts of hair-like protrusions on their surfaces. A sound wave entering the cochlea causes the hair-like protrusions to bend, stimulating the hair cell to send electrical signals to the brain. A type of neuron that sends sensory information from the periphery into the brain is called an ‘afferent’. Communication from the IHCs via their afferents into the brain is well understood to be primarily responsible for our sense of hearing. OHCs are understood to have an indirect activity, contained within the cochlea: they have the ability to boost the sound wave for the benefit of the IHCs. This is referred to as ‘cochlear amplification’. Essentially, OHCs allow us to hear low-level sounds that we otherwise could not. The OHCs are particularly susceptible to death as a result of loud noise exposure, certain medications, or aging. This is problematic as hair cells do not regenerate, resulting in a common form of permanent hearing loss.
OHCs also have afferents that appear to be able to transmit information into the brain, however, the function of these afferents has been mysterious for decades. The OHC afferents only transmit information to the brain when sound in the cochlea is already quite loud, perhaps greater than 85 decibels. We propose three possible functions for the OHC afferent: 1) they have the ability to regulate the activity of OHCs as they function in cochlear amplification, 2) they provide a mechanism, perhaps resembling a reflex, to protect the fragile OHCs from death when loud sound is in the cochlea, or 3) they mediate a sense of auditory pain, informing the brain when sound levels are approaching dangerous levels.
The OHC afferents have proven to be very difficult to study. We propose to study the OHC afferents in mice using a completely novel genetic approach designed to selectively prevent the OHCs from transmitting any information to the OHC afferents. Using the newly created mice, we will be the first to begin to address the possibilities proposed above. The most exciting outcome would be if the OHC afferents are shown to have a function in the protection against OHC death. If true, than it suggests that this system could be manipulated for therapeutic benefit, to protect the hearing of those at risk for hearing loss.
Pictured, Clockwise from top left: T. Overath, J. Stohl, M. Murias, L. Collins
Tobias Overath, PhD
Assistant Research Professor, Duke Institute for Brain Sciences
Josh Stohl, PhD
Director, North American Research Laboratory
Adjunct Assistant Professor, Department of Electrical and Computer Engineering
Leslie M. Collins, PhD
Professor, Department of Electrical and Computer Engineering
Michael Murias, PhD
Assistant Research Professor, Duke Institute for Brain Sciences
Optimizing cochlear implant sound processor configurations via neural response properties to improve speech comprehension
Summary: For the ~1.5 million Americans who are deaf in at least one ear, the cochlear implant (CI) is the most successful sensory prosthetic implant to help them regain hearing; however, while some of the ~500,000 people in the US with CIs achieve near-perfect speech comprehension in ideal listening situations, others continue to struggle and require lengthy appointments to have their CIs programmed. This project aims to optimize CI configuration by recording neural responses in the brains of CI users while they listen to speech. These neural responses may then be used as a guide to re-program the CI to enhance the implant’s performance, reducing the need for repeated adjustments.
Enrique Perez, Team: Perez, Dr. Simon Angeli, Dr. Esperanza Bas
Enrique Perez, MD, MBA
Department of Otolaryngology Head and Neck Surgery
University of Miami Miller School of Medicine, Florida
High-resolution contrast-enhanced microendoscopy in cholesteatoma surgery: safety, efficacy and feasibility
Summary: Frequent infections of the ear in some individuals can lead to the development of a cyst known as a cholesteatoma. Cholesteatomas grow behind the eardrum and often become infected. Over time they may destroy the structures in our ear that help us hear. Surgery is the only way to correct the problem. Otologists, or ear surgeons, often have trouble removing the entire wall of a cholesteatoma cyst in the operating room, and it is common to see cholesteatomas come back. Hence, otologists often bring patients back to the operating room for a “second look” surgery to make sure all of the cholesteatoma has been removed.
Our research involves the development of a new method to reduce the risk of leaving any cholesteatoma behind using a fluorescent solution (Proflavine) that lights up the cholesteatoma. This new technique has never been tested in animals or humans and its safety and efficacy needs to be investigated. Therefore our research team has designed several studies to test how safe and effective it is to use Proflavine in the ear.
Molecular & Human Genetics
Baylor College of Medicine, Houston
Identification of genes for non-syndromic rare congenital inner ear malformations in children
Summary: This project aims to study the molecular basis of rare ear malformations in children. Genetic studies of sensorineural hearing loss have been the focus of many geneticists in the last decades. Though this has educated us tremendously about the inner ear and hearing in health and disease, rare abnormalities in cochleovestibular anatomy can also have a devastating impact on hearing and language development. These latter have so far been overlooked by genetic studies. (Read more)
In the era of next-generation sequencing and with the increasing sensitivity of imaging techniques, rare ear malformations are now more effective to identify and characterize. To elucidate the pathogenic mechanisms responsible for rare ear anomalies in children, we will use an integrative next-generation sequencing approach based on DNA and RNA sequencing.
Each of these individuals can provide a unique and invaluable insight into the development of the ear or the normal hearing process. In addition, abnormalities in cochleovestibular anatomy can provide challenges for cochlear implantation, and a genetic diagnosis and understanding of the molecular basis might help with identifying the correct therapeutic intervention for unique affected individuals.
Erika Skoe, PhD (left)
Department of Speech, Language and Hearing Sciences
University of Connecticut
Jennifer Tufts, PhD (right)
Department of Speech, Language and Hearing Sciences
University of Connecticut
Biological indices of noise exposure in the clinically-normal ear
Summary: Many individuals are routinely exposed to high-intensity sound as part of their occupational and/or leisure activities. Both chronic and short-term overexposure to sound can damage the auditory system in ways that are not necessarily evident on a standard hearing test.
The long-term goal of our multi-lab collaboration is to develop a rapid screening method for detecting the very early stages of noise-induced damage to the auditory system. (Read more) Development of a clinical screening method could potentially prevent further decline of peripheral and/or central function through individually-tailored audiological counseling and services. With this goal in mind, we will repeatedly measure noise exposure and auditory system function in young adults over a four-month timeframe. Individuals’ sound exposure levels will be measured using a noise dosimeter, a small sound level meter worn by each participant. We will be tracking fluctuations in auditory system function during high and low points of noise exposure using a test battery that includes auditory brainstem responses, high-frequency audiometry, and circulating blood levels of prestin, a protein associated with inner ear function. This combination of auditory assessments will provide new insight into the time course of noise-induced damage to the auditory system.
Spencer B. Smith, PhD, AuD
Auditory Neuroscience Lab
Northwestern University, Evanston, Illinois
Investigating the Relationship between Binaural Hearing and Speech-in-Noise Performance in Middle-Aged Listeners
Summary: A common complaint reported by middle-aged patients seeking audiologic services is an emergent decline in speech-in-noise (SIN) perception. Paradoxically, many of these patients demonstrate normal hearing thresholds or mild hearing loss that is incommensurate with the severity of their complaints. The standard audiologic test battery fails to provide these patients with answers regarding the etiology of their deficits and leaves audiologists with no objective information upon which to base counseling and treatment recommendations. (Read more) To improve the standard of hearing care for these patients – a key mission of the American Hearing Research Foundation – more sophisticated and easily implementable clinical tools are needed.
Over the past decade, advances in hearing science have led to more sophisticated tests to understand potential SIN deficits, including those that evaluate cochlear health, neural processing, and cognition. Surprisingly, binaural hearing — a key contributor to real-world SIN performance requiring exquisite neural temporal processing ability — has yet to be incorporated into these clinical batteries. Recent evidence indicates that deficits in binaural hearing may begin in middle age (30-60 years) in parallel with the emergence of SIN complaints, supporting the idea that it might underlie some patients’ SIN deficits. Despite a large experimental literature on psychophysical tests of binaural hearing, however, an efficient and reliable clinical assay of binaural hearing function currently does not exist.
The broad goals of this research are to 1) develop objective (electrophysiologic) indices of binaural hearing acuity and 2) investigate relationships between these indices and SIN performance. To achieve these goals, a comprehensive test battery including auditory evoked potentials will be used to examine neural processing of binaural timing cues to simple (tones) and complex (speech) stimuli in middle-aged adults. Further, the relationship between these measures and SIN perceptual performance on tests requiring binaural hearing will be investigated. The long-term goal of this research is not only to understand how binaural hearing acuity influences real-world perception but to develop easily administered objective clinical tests of binaural hearing function. Such tests would improve diagnostics and would also be beneficial for verifying and fine-tuning binaural hearing aid and cochlear implant fittings.