General Hearing Health

Soumen Roy, Ph.D.

Soumen Roy, Ph.D.

National Cancer Institute
High-dimensional analysis of cochlear immunity and cisplatin-induced inflammation

Cisplatin is a life-saving chemotherapy drug but has serious side effects, including causing hearing loss in 40 to 80 percent of cancer patients. Cisplatin enters the cochlea through systemic circulation and gains access to inner ear sensory hair cells after disrupting the protective blood-labyrinth-barrier (BLB). A damaged BLB also means a greater invasion of CD45(+) leukocytes (white blood cells), causing inflammation and, ultimately, hearing loss. We hypothesize that a defined subset of innate immune cells regulates hair cell death by controlling cisplatin-induced inflammatory pathways within the cochlea. Our preliminary data suggest that the cochlea has a different amount of defined leukocytes compared with blood-borne leukocytes. In addition, the data suggest that immune cells that regulate cochlear inflammation may play a role in overall ototoxicity. Understanding cochlear immunity and the interaction of immune cells with other sensory cells will shed light on ototoxicity research and its prevention.

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Regie Lyn P. Santos-Cortez, M.D., Ph.D.

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Regie Lyn P. Santos-Cortez, M.D., Ph.D.

Baylor College of Medicine
Identification of genes that predispose to chronic otitis media in an indigenous population

The study aims to identify genes predisposing to otitis media by studying gene variants that are identified from a complex pedigree within an indigenous population that has a high prevalence of chronic otitis media. The study population is ideal for gene mapping due to the limited number of founders and marriages only within the indigenous population. Next-generation sequencing will be performed in order to quickly and cost-effectively detect the causal genetic variants for otitis media that fall within the mapped genomic region. The discovery of gene variants predisposing to otitis media opens great possibilities towards increased knowledge of pathophysiology, prediction of the likelihood of otitis media through genetic diagnosis, and development of innovative treatments for otitis media.

Research areas: otitis media, genetics

Long-term goal of research: The discovery of genes predisposing to otitis media will lead to increased knowledge of the disease process behind otitis media and development of new diagnostic and treatment strategies for otitis media. The study findings are expected to benefit not only the indigenous population but also otitis media patients from other populations, as the genes that will be found can be followed up in other populations and as new therapies are developed through knowledge of genes predisposing to otitis media.

Regie-Lyn Santos-Cortez, M.D., Ph.D. graduated from the University of the Philippines Manila College of Medicine – Philippine General Hospital for both her medical education and residency in otorhinolaryngology. She studied genetic epidemiology in Erasmus Medical Centre Rotterdam, the Netherlands and did most of her PhD work on the genetics of non-syndromic hearing impairment at the Leal lab at Baylor College of Medicine, Houston, Texas, USA. She is now Assistant Professor at the Center for Statistical Genetics, Department of Molecular and Human Genetics at Baylor.

Takunori Satoh, Ph.D.

Takunori Satoh, Ph.D.

Purdue University

Gene discovery related to congenital deafness

Congenital deafness in humans occurs in approximately 1 in 1,000 live births, yet few of the responsible genes are known. This study aims to discover new genes important to the development of the auditory system using zebrafish to determine if they correspond to genes underlying congenital deafness in humans. Utilizing a new process, this study hopes to facilitate gene discovery then determine the involvement of the genes in the development of the auditory system.

Iris Schrijver, M.D.

Iris Schrijver, M.D.

Stanford University School of Medicine

The functional impact of single and dual expression of GJB2 missense variants V271 and E114G: An exploration of pathogenic effects on hearing

It is difficult to predict the consequences of DNA alterations that result in the replacement of one protein building block by another. Yet, an important aspect of genetic testing is to predict whether a DNA change is harmful or not. With this project, we will solve this dilemma for two relatively common variants in the connexin 26 gene. Interestingly, it appears that these two variants do not contribute to hearing loss when opposite of a disease causing change separately, but when they occur together opposite such a change, there is hearing loss as if these changes have an additive deleterious effect. By using techniques in which we are experienced, we plan to continue our research in hearing loss and directly observe whether and how these variants affect the connexin 26 protein functions within the cell. We will determine the effect on the amount of connexin 26 proteins, on localization and transport within the cell, and on function by establishing whether the essential communication channels between cells are still formed. This work will enable the correct clinical interpretation of these commonly observed changes, and can help begin to link DNA changes to protein effects and clinical symptoms in patients with hearing loss.

Rebecca Seal, Ph.D.

Rebecca Seal, Ph.D.

University of Pittsburgh
Role of outer hair cell glutamate release in cochlear function and dysfunction

Outer hair cells are vital for normal hearing. Although the cells are known to amplify the cochlear response to sound using an electromotile mechanism, they also signal to type II spiral ganglion neurons through the regulated release of glutamate. However, the function of this signaling remains unknown. Similar to inner hair cells, glutamate signaling by outer hair cells may influence sound transmission as well as the maintenance of spiral ganglion afferents. In the adult, cholinergic efferents play a critical role in maintaining outer hair cell viability and the innervation pattern of these fibers may also be influenced by the released glutamate. Thus, there are several potential mechanisms by which loss of glutamate signaling by outer hair cells could cause hearing loss. This proposal aims to address these possibilities.

Research area: fundamental auditory research

Long-term goal of research: To provide new information about the role of hair cell signaling in hearing and in disorders of the auditory system including hearing loss. These analyses will inform decisions on therapeutic strategies for the restoration of hearing and for other disorders that may be derived from aberrant cochlear function.

Rebecca Seal Ph.D. received her Ph.D. in Neuroscience from Oregon Health and Sciences University and completed her postdoctoral training in sensory circuits at the University of California, San Francisco. She is currently an Assistant Professor in the Department of Neurobiology at the University of Pittsburgh.

Armin Seidl, Ph.D.

Armin Seidl, Ph.D.

Click to download a PDF of Dr. Seidl’s Meet the Researcher profile.

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Gail M. Seigel, Ph.D.

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Gail M. Seigel, Ph.D.

University at Buffalo, the State University of New York
Targeting microglial activation in hyperacusis

Hyperacusis is a hearing condition in which moderate-level noise becomes intolerable. The Centers for Disease Control estimates that nearly 6 percent of the U.S. population experiences some form of hyperacusis, ranging from mild discomfort to severe medical disability, with a diminished quality of life. There is currently no cure for hyperacusis. Therefore, there is a pressing medical need for targeted treatment approaches for the permanent relief of hyperacusis. This study will focus on the involvement of inflammation in the sound processing centers of the brain following noise exposure by using anti-inflammatory drugs to attempt to reduce inflammation and prevent hyperacusis after noise exposure. Results from this study will test the feasibility of anti-inflammatory drugs as a potential therapy for hyperacusis and hearing loss caused by excessive noise exposure.

Valeriy Shafiro, Ph.D.

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.

Jun Shen, Ph.D.

Jun Shen, Ph.D.

Brigham and Women’s Hospital; Harvard Medical School
An integrated paradigm for efficient hearing loss gene discovery

Knowing the genetic cause of hearing loss allows early diagnosis before the onset of noticeable symptoms. It also informs the choice of optimal management plans, and predicts risks for relatives including future babies. We aim to identify novel hearing loss genes by studying three large families with hereditary hearing loss from an isolated population. We will integrate new High- Throughput (HTP) sequencing technology with family-based analyses and prior research findings concerning hearing into the Shared Harvard Inner Ear Laboratory Database (SHIELD). This integrated approach will enable efficient identification of one or more hearing loss genes in these families. The discovery of novel genes will increase our knowledge, enable early diagnosis, and ultimately lead to improved patient care.

Research area: Fundamental auditory research

Long-term goal of research: To translate genetic research findings into accurate and sensitive clinical molecular diagnostic tests to improve care for patients.

Yu-chi Shen, Ph.D.

Yu-chi Shen, Ph.D.

University of Michigan

The role of MIF in zebrafish inner ear development

We hypothesize that MIF plays a major role in otic development, specifically in neurite outgrowth and survival of the developing SAG neurons in the inner ear. We have found that MIF is expressed in the mammalian (mouse) inner ear, the chick inner ear and in the model system we have chosen to study, the zebrafish inner ear. Zebrafish auditory system development recapitulates many aspects of early mammalian inner ear development and neurogenesis. More importantly, the same molecules that are active in the mammal are active in the zebrafish and the zebrafish inner ear development is both easier to study and is extremely rapid. We will examine early survival and maturation factors for the SAG and use advanced imaging to trace SAG precursor cell movements from the otic vesicle to the ganglion. Preliminary studies using in situ hybridization demonstrated that MIF and MIF-like genes and their receptors are expressed in zebrafish SAG and developing inner ear. Our experiments will examine whether MIF and MIFlike gene loss-of-function using morpholino antisense oligonucleotides (MOs) affects SAG development and whether this loss of function can be "rescued" by introducing MIF RNA.

Jung-Bum Shin, Ph.D.

Jung-Bum Shin, Ph.D.

Oregon Hearing Research Center and Vollum Institute

Proteomic analysis of stress-response proteins in the sensory hair bundle

This study will examine the molecular mechanisms that underlie auditory mechanotransduction. A principal understanding of this process is essential for studying the pathophysiology of hearing loss. We will address the question whether the hair bundle possesses special mechanisms that protect it from harmful environmental influences such as mechanical stress and free radicals.

Olga Stakhovskaya, M.D., Ph.D.

Olga Stakhovskaya, M.D., Ph.D.

Click to download a PDF of Dr. Stakhovskaya’s Meet the Researcher profile.

Zlatka P. Stojanova, Ph.D.

Zlatka P. Stojanova, Ph.D.

House Research Institute
Epigenetic Regulation of the Atoh1 gene during development and regeneration of the mammalian organ of Corti

The Atoh1 gene is both necessary and sufficient for auditory hair cell formation during normal development. It is also one of the first genes to be upregulated during regeneration in non-mammalian vertebrates. The project is investigating novel mechanisms of Atoh1 gene regulation that involve epigenetic modifications (not due to changes in DNA sequence). During the 2nd year renewal we will analyze the mechanistic links between the discovered epigenetic state of the Atoh1 gene and the Atoh1 gene expression.

Research areas: hair cell regeneration, genetics

Long-term goal of research: To better understand how is Atoh1 gene regulated in order to reverse the failure of hearing regeneration in the mammalian organ of Corti.

Arminda Suli, Ph.D.

Arminda Suli, Ph.D.

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.

Chin-Tuan Tan, Ph.D.

Chin-Tuan Tan, Ph.D.

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.

Xiaodong Tan, Ph.D.

Xiaodong Tan, Ph.D.

Northwestern University
Oto-Protection of Honokiol Against Cisplatin-Induced Ototoxicity

Cisplatin is a common chemotherapy medication known to be ototoxic (damaging to hearing), but most proposed drugs to counteract this side effect compromise the antitumor effects of cisplatin. Honokiol is an antitumor agent derived from the magnolia plant that has been shown to have synergistic effects with cisplatin in cancer treatment because it activates an enzyme that protects healthy cells and suppresses tumor cells. As a result, honokiol may have a strong protective effect for cochlear hair cells. This study will investigate the hearing protective properties of honokiol using tissue cultures in the lab as well as through direct drug administration in an animal model.

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Pei-Ciao Tang, Ph.D.

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Pei-Ciao Tang, Ph.D.

University of Miami Miller School of Medicine
Elucidating the development of the otic lineage using stem cell-derived organoid systems

One of the main causes of hearing loss is the damage to and/or loss of specialized, cochlear hair cells and neurons, which are ultimately responsible for our sense of hearing. Stem cell–derived 3D inner ear organoids (lab-grown, simplified mini-organs) provide an opportunity to study hair cells and sensory neurons in a dish. However, the system is in its infancy, and hair cell–containing organoids are difficult to produce and maintain. This project will use a stem cell–derived 3D inner ear organoid system as a model to study mammalian inner ear development. The developmental knowledge gained will then be used to optimize the efficacy of the organoid system. As such, the results will progress our understanding of how the inner ear forms and functions, with the improved organoid system then allowing us directly to elucidate the factors causing the congenital hearing loss.

Wenxue Tang, M.D.

Wenxue Tang, M.D.

Emory University School of Medicine

The molecular diversity of gap junction channel systems in the cochlea

The long-term objective of this study is to understand how molecular mechanisms of different subtypes of connexins (Cxs) contribute to cochlear functions. Connexins (Cxs) are a family of proteins constituting the gap junctions (GJs). GJs allow direct intercellular exchanges of nutrients, inorganic ions, signaling molecules. The importance of Cxs in hearing functions has been revealed by large amount of genetic linkage studies showing that mutations in Cx genes are associated with about half of patients with childhood nonsyndromic hearing losses. Mutations in Cx26 are responsible for most of the cases. However, mutations in a myelinating Cx (Cx32) have also been linked to Charcot-Marie-Tooth syndrome that includes hearing defects in many cases. Despite their importance in hearing, we know very little about molecular mechanisms that GJs play in the cochlea.

Osama Tarabichi, M.D., MPH

University of Iowa

The role of inner ear lymphatics in the foreign body response to cochlear implantation

To develop spoken language, infants must rapidly process thousands of words spoken by caregivers around them each day. This is a daunting task, even for typical hearing infants. It is even harder for infants with cochlear implants as electrical hearing compromises many critical cues for speech perception and language development. The challenges that infants with cochlear implants face have long-term consequences: Starting in early childhood, cochlear implant users perform 1-2 standard deviations below peers with typical hearing on nearly every measure of speech, language, and literacy. My lab investigates how children with hearing loss develop spoken language despite the degraded speech signal that they hear and learn language from. This project addresses the urgent need to identify predictors of speech-language development for pediatric cochlear implant users in infancy.

Shikha Tarang, Ph.D.

Shikha Tarang, Ph.D.

Creighton University
Transient and Regulated Dominant-Negative RB1 Inhibition to Regenerate Hair Cells

Our ability to hear and communicate depends primarily on the sensory hair cells (HCs) and their associated spiral ganglion neurons (SGNs). Unfortunately, mammalian HCs and SGNs are not naturally replaceable, and their loss results in neurosensory hearing loss and balance impairment. To this date, any attempts to regenerate lost sensory HCs have been challenged by the early embryonic lethality of complete knockout mice or massive cell death after conditional deletion of targeted genes. In this light, we sought to design a new system that combines the inducible nature of an antibiotic-controlled system with the lysosomal fusion protease pre-procathepsinB (CB) to generate an inducible, temporal, and reversibly conditional mouse model. To build upon our laboratory’s expertise, we applied this technology to generate a mouse model carrying a transgenic version of the of the retinoblastoma (Rb1) gene. The Rb1 gene is a key component of cell cycle regulation. In addition to its role in cell proliferation, Rb1 expression in the inner ear also affects differentiation and survival of HCs and their associated supporting cells (SCs). Rb1 deletion leads to the production of supernumerary HCs and SCs. However, just like a number of other genes considered potential candidates for HC regeneration, complete and permanent elimination of Rb1 results in massive apoptosis, and as such, should be avoided at all costs. This study will allow us to characterize this newly generated model of transient and reversible gene ablation and gather information supporting pre-clinical studies on HC regeneration.

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