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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.

Sandeep Sheth, Ph.D.

Sandeep Sheth, Ph.D.

Southern Illinois University School of Medicine
Cisplatin-induced oxidative stress down-regulates strial Na+/K+-ATPase and endocochlear potential

Cisplatin is a widely used chemotherapy treatment for various solid tumors. Unfortunately, its use sometimes results in permanent hearing loss. Understanding the pathophysiology of cisplatin ototoxicity (toxicity to the ear) is crucial for the development of novel treatments to combat this serious side effect.

Preliminary studies from our lab suggest that cisplatin appears to reduce the sodium/potassium activity of the cochlear fluid maintained by the stria vascularis, an important tissue in the inner ear, which leads to hearing damage. However, this suppressive effect by cisplatin may be restored through epigallocatechin gallate (EGCG), a green tea extract that is an antioxidant with anti-inflammatory properties. This project aims to investigate the potential of EGCG in the treatment of cisplatin-induced hearing loss.

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.

Marina Silveira, Ph.D.

Marina Silveira, Ph.D.

University of Texas at San Antonio

Age-related changes in neuromodulatory signaling in the auditory midbrain

Age-related hearing loss is the most common form of hearing loss in older adults. Age-related hearing loss causes difficulty understanding speech in noisy environments. Consequently, hearing loss has a major negative impact on quality of life and leads to social isolation, loneliness, and is a significant risk factor for dementia and Alzheimer’s. It is well known that age-related hearing loss shifts the excitatory-inhibitory balance in the inferior colliculus to favor excitability. This enhancement in excitability can contribute to pathological conditions such as tinnitus and poor temporal processing. However, the mechanisms that regulate this enhanced excitability in the inferior colliculus are unclear. A major neuromodulator called serotonin has been shown to regulate the excitatory-inhibitory balance in other brain regions. In preliminary studies for this proposal, we found that serotonin strongly influences the activity of a class of inhibitory neurons in the inferior colliculus that express neuropeptide Y. Here, we will test the hypothesis that dysfunction in serotonergic and neuropeptide Y signaling underlies enhanced excitability in the inferior colliculus in age-related hearing loss. Because the serotonergic system is a common target for pharmaceuticals, our results will also provide foundational insights that might guide future pharmacological interventions for age-related hearing loss.

Nirmal Kumar Srinivasan, Ph.D.

Nirmal Kumar Srinivasan, Ph.D.

Towson University
Understanding and decoding CAPD in adults

Understanding speech in complex listening environments involves both on top-down and bottom-up processes. Central auditory processing disorder (CAPD) refers to a reduction in the efficiency and effectiveness of how the central nervous system utilizes the presented auditory information. It is characterized by a diminished perception of speech and non-speech sounds that is not attributable to peripheral hearing loss or intellectual impairment. Hearing loss and CAPD can adversely affect everyday communication, learning, and physical well-being.

A substantial number of adults evaluated for CAPD complain about difficulties in resolving auditory events that are similar to that of individuals with hearing impairment. These individuals have audiograms that are similar to those of age-matched individuals. Since the audiogram is the primary tool used in the clinic to distinguish people with hearing loss, it is imperative to understand the fundamental differences observed in behavioral experiments for individuals with CAPD and individuals with hearing loss.

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.

Wei Sun, Ph.D.

Wei Sun, Ph.D.

University at Buffalo

FOXG1 gene mutation-caused hyperacusis—a novel model to study hyperacusis

Hyperacusis is a common symptom in children with neurological disorders such as autism spectrum disorder, Williams syndrome, Rett syndrome, and FOXG1 syndrome (FS). The cause of hyperacusis in these neurological disorders has not been fully discovered. FOXG1 mutation is a recently defined, rare and devastating neurodevelopmental disorder. MRI studies show a spectrum of structural brain anomalies, including cortical atrophy, hypogenesis of the corpus callosum, and delayed myelination in children with FS. However, the impact of the FOXG1 mutation on the central auditory system and hyperacusis is largely unknown. Children with FS show signs of hyperacusis, including becoming startled, upset, and even experiencing seizures from loud sounds. The mouse model of FOXG1 mutation provides a novel model to study neurological dysfunction in the central auditory system resulting in hyperacusis. In this project, we will use a mouse model developed by colleagues at University at Buffalo that replicates gene mutations in FS children to study hyperacusis. In our preliminary studies, we found that the mutant mice showed a lack of habituation in the startle tests and an aversive reaction to loud sounds in the open field test. We also found that the cortical neurons showed reduced neural activities and prolonged responses to sound stimuli, suggesting hypoexcitability and a lack of adaptation to sound stimuli. The results point toward a novel neurological model of hyperacusis compared with the current “central gain” theory. Our findings will provide mechanistic insights into the role of the FOXG1 gene on hyperacusis and shed light on detecting potential therapeutic targets to alleviate hyperacusis caused by FS and other neurological disorders.

Ian Swinburne, Ph.D.

Ian Swinburne, Ph.D.

Harvard Medical School
Development and Physiology of the Endolymphatic Duct and Sac in Zebrafish

Abnormalities in our sense of hearing and balance are incapacitating in the extreme, and, when subtle, cause psychological distress. Meniere’s disease is an inner ear disease with unclear causes that is inferred from episodes of vertigo, hearing loss, tinnitus, and the sensation of fullness in the ear that can last two to four hours. An unstable inner ear environment is believed to underlie Meniere’s disease. Recently, Swinburne has developed methods to image the live development and physiology of the portion of the Zebrafish ear conserved in humans and believed to be dysfunctional in Meniere’s disease: the endolymphatic duct and sac. With these methods, Ian hopes to gain basic understanding of how the inner ear’s environment is normally maintained and how a defect can lead to a disease.

Classifying the endolymphatic duct and sac cell types and their gene sets using high-throughput single-cell transcriptomics

To understand how the inner ear endolymphatic duct and sac stabilize the inner ear’s environment and to identify ways to restore or elevate this function to mitigate or cure Ménière's disease. The endolymphatic duct and sac play important roles in stabilizing a fluid composition necessary for sensing sound and balance. The recurrent vertigo in Ménière's is likely caused by a malfunction of the endolymphatic sac, causing volume or pressure changes in the inner ear.

Swinburne recently found that the typical-functioning endolymphatic sac periodically inflates and deflates like a balloon, and that specialized cell structures in the sac appear to transiently open, causing the deflation of the endolymphatic sac. The sac, then, appears to act as a relief valve to maintain a consistent volume and pressure within the inner ear. This project will generate a list of endolymphatic sac cell types and the genes governing their function, which will aid in Ménière's diagnosis (which can be delayed due to the range of fluctuating symptoms) and the development of a targeted drug or gene therapy.

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.

Zhengquan Tang, Ph.D.

Zhengquan Tang, Ph.D.

Oregon Health & Science University
Hyperexcitability dependent on Neuromodulatory state in the cochlear nucleus

Tinnitus affects approximately 50 million people in the USA, and millions more worldwide. However, the mechanisms underlying tinnitus are poorly understood. The dorsal cochlear nucleus (DCN), one of the first stations of the ascending auditory pathway, receives dense serotonergic input. Recent evidence indicates that the DCN may be a site of central tinnitus, and it is possible that serotonin might play a role in the generation or modulation of central tinnitus. Moreover, serotonin reuptake inhibitors (SSRIs) typically used as antidepressants in the treatment of depression and anxiety disorders, have been explored as a treatment for tinnitus. The goal of this research is to identify the cellular targets of serotonin and SSRIs in the DCN and understand their functional roles. The ultimate goals of this research are to understand how serotonin influences the output of the DCN, and whether serotonin may have a role in tinnitus.

Research area: Tinnitus

Long-term goal of research: To understand how different neuromodulators control the neural activity in the central auditory system and their role in pathological auditory processing.

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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