University of Iowa
Investigating the Role of CaBP1 in KCNQ4 Channel Modulation

KCNQ4 potassium channels play an important role in controlling the responsiveness of auditory hair cells to sound stimulation. Mutation of the gene encoding this channel cause deafness in humans, which is typically due to improper functioning of these channels in the ear. I have identified a novel interaction between Ca2+ binding protein 1 (CaBP1), which is highly expressed in auditory hair cells, and KCNQ4. The goal of this research is to evaluate the functional consequences of this interaction on the cellular localization and biophysical properties of KCNQ4 channels in auditory hair cells.

Research area: fundamental auditory research

Long-term goal of research: To understand at the molecular level how hair cells function normally in sound detection and develop novel therapeutic strategies for treating patients with inherited forms of hearing loss.

University of Virginia
Susceptibility to chronic otitis media: translating gene to function

Each year in the United States, over $5 billion is spent on healthcare for inflammation of the middle ear (ME) known as otitis media (OM) in children. Some children develop chronic middle ear infections known as chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our goal is to find genetic factors that increase risk for COME/ROM in children. The discovery of causal variants would increase knowledge of novel genes and pathways involved in COME/ROM pathogenesis.

Research areas: otitis media, genetics

Long-term goal of research: Findings from our research are expected to improve the clinical prevention of chronic infections; therefore decreasing pediatric antibiotic use, surgery, and deafness.

Stanford University
Characterization of Wnt-responsive progenitor cells in the mammalian cochlea

Hearing loss is a common sensory disorder affecting nearly 50 million adults in the United States alone. The majority of hearing loss is caused by the loss of the inner ear sensory hair cells, which, in mammals, lack the ability to regenerate. In this proposal, we will gain insights into the regenerative potential of the mammalian cochlear hair cells, with long term goal to improve the current treatment of hearing loss via hair cell regeneration. The Wnt signaling pathway has been found to play a crucial role in maintaining the stem cell population in several organ systems. Recently our laboratory has found a transient expression of active wnt signals in the mouse cochlea, and found 2 inner ear progenitor cell populations marked by two Wnt downstream target genes. This project has been designed to systematically investigate the role of the Wnt pathway in maintaining these two Wnt responsive progenitor cell populations.

Research area: hair cell regeneration

Long-term goal of research: To use hair cell regeneration and cell-base therapy to treat patients with sensorineural hearing loss.

Baylor College of Medicine
Development of Biomarkers to Study Strial Development and Degeneration

The sensory hair cells of the cochlea are able to detect sound vibrations. Hair cells need a source of potassium that helps them to convert sound energy into electrical energy that is sent to the brain. Hair cells in our cochlea are bathed in a potassium-rich fluid called endolymph, and the potassium is constantly pumped into the endolymph by a specialized group of cells in the cochlea called the stria vascularis. As humans get older, the stria vascularis can degenerate, and so the “battery” that supplies potassium to the cochlea runs down, and we lose our hearing. The goal of this project is to understand how the stria vascularis develops, and to devise ways of looking at changes in this structure with age.

Research areas: the development and regeneration of the inner ear, stria vascularis development

Long-term goal of research: We hope this knowledge may allow us to repair or slow down damage to the cochlea and lessen the effects of age-dependent hearing loss.

Washington University
Role of FGF's in Cochlear Sensory Epithelium

Congenital sensorineural hearing loss is one of the most common hereditary disabilities, affecting 1 in 1000 children. Fgf20 null mice have congenital hearing loss associated with loss of sensory cells, and inactivation of both Fgf9 and Fgf20 result in a shortened cochlea. The goal of our research is to understand the cellular and molecular functions of Fgf9 and Fgf20 in inner ear development in vivo. The ultimate goal of this research is to learn how to direct the regeneration of malformed or damaged sensory tissue to restore or improve hearing.

Research area: hair cell regeneration

Long-term goal of research: My long term goal is to understand how Fgf signaling regulates the development, maintenance and repair of sensory hair cells and supporting cells in the cochlea. Due to lack of regenerative ability in humans after loss or dammage of hair cells, it is critical to identify signals that can reactivate developmental pathways and thus permit repair and regeneration of the damaged cochlea. Studying the mechanisms that regulate cochlear development will provide valuable clues about molecules that can be tested for regenerative activity and will thus benefit future translational studies aimed at inducing hair cell regeneration in adult humans.

University of Michigan
Investigating the role of Chd7 during noise-induced hearing loss

Mice born with loss of Chd7, the gene mutated in human CHARGE syndrome, exhibity middle ear defects and resistance to acoustic trauma. Preliminary results show that deletion of Chd7 in adult mice (using tamoxifen inducible Cre line) also results in variable resistance to acoustic trauma, even in the absence of middle ear defects. This suggests important functions for Chd7 in regulating hair cells and neuronal integrity in adult cochlea. The objective of this research is to identify how loss of Chd7 influences susceptibility to acoustic trauma in the mature cochlea.

Research area: noise-induced hearing loss (NIHL)

Long-term goal of research: to help identify novel genes and molecular pathways involved in protection from NIHL and provide rationale for designing new therapies.

University of Iowa
Misexpression of Neurog1 combined with delayed deletion of Atoh1 provides a novel model

Contemporary research is focusing on the regeneration of hair cells in hearing loss using Atoh1. Reconstitution of the organ of Corti requires proper organization of the two types of hair cells, inner and outer hair cells, as well as supporting cells. Recent data showed that level of Atoh1 determines the degree of survival of different types of hair cells. Jahan’s previous work demonstrated the survival of some organ of Corti-like cells without Atoh1 if replaced by a closely related transcription factor, Neurog1. It is now Jahan’s intent to investigate the effect of Atoh1 substitution with Neurog1 combined with a delayed loss of Atoh1 expression in viable animals. This combined mutant offers for the first time a critical test of presumed causalities of molecular mechanism that may regulate the patterning of the organ of Corti, including hair cell and supporting cell differentiation.

Research area: Hair Cell Regeneration

Long-term goal of research: To define the correct dose and duration of Atoh1 expression for type-specific hair cell development which will provide novel insights into hair cell regeneration.

Rutgers University
Identification of Transcription Factors for Hair Cell Regeneration

In mammals, when hair cells die from ototoxic drugs or loud noises, they are not replaced. Kwan’s efforts are focused on identifying transcription factors that promote repopulation and replacement of lost sensory hair cells. Transcription factors are DNA binding proteins that play crucial roles in global gene regulation. By repurposing transcription factors that are normally expressed during hair cell development, he plans to promote regeneration by controlled cell division to repopulate lost hair cells before differentiating nascent cells into hair cells.

Research area: hair cell regeneration

Long-term goal of research: To use a cocktail of small molecules that activates expression of transcription factors or their associated signaling pathways in order to promote functional auditory hair cell regeneration and alleviate hearing loss.

Rockefeller University
Ascertaining the contribution of Piezo proteins to Mechano-transduction in Zebrafish hair cells

The proteins that mediate the transformation of mechanical forces into electrical signals within the sensory cells that convey the senses of hearing and balance have yet to be identified. This lack of knowledge has undoubtedly hindered the identification of therapeutic compounds capable of alleviating the complications that arise from disorders in hearing and balance, such as deafness and vertigo. Recently, a member of the novel piezo protein family has been shown to contribute to cutaneous mechano-sensation, raising the possibility that related family members may contribute to hearing and balance. Dr. Low will utilize the simple vertebrate commonly known as zebrafish, to address this possibility.

Research area: Fundamental Auditory Research

Long term goal of research: To identify therapeutic agents that can restore normal hearing and balance in individuals who have either lost these senses, or suffer from conditions caused by abnormal activity in the sensory cells that mediate them.

Sean Low Ph.D. received a B.S. in Cellular and Molecular Biology in 2001, and a Ph.D. in Neuroscience in 2008 from the University of Michigan. Desiring to focus on sensory transduction, Low sought out a postdoctoral position in the Saint-Amant lab at the University of Montréal from 2009 – 2011, where he examined the role of a Piezo protein in cutaneous mechano-transduction. These studies evolved into an interest in mechano-transduction processes in general, and a second postdoctoral position with Dr. Hudspeth at The Rockefeller University beginning in 2011.

Washington University
Cellular and Genetic Bases of Age-Associated Strial Degeneration and EP decline in NOD congenic mice

The electric currents that run through cochlear sensory cells are largely driven by a specialized cochlear structure called the stria vascularis. The work of the stria requires a lot of energy, so that it is densely vascularized (hence the name). Loss of strial blood vessels is thought to be a common cause of age-related hearing loss. Not everyone shows signs of this kind of pathology, however, so that there must be forms of certain genes carried by some people that act as ‘risk’ genes. People who carry ‘risk’ genes may be more likely to experience loss of strial blood vessels, and ultimately loss of the stria itself. In 2008 we discovered that a particular breed of mice (NOD mice) start out with a normal stria, but then show loss of strial vessels, followed by loss of the stria beginning from both ends of the cochlea and progressing toward the middle. These changes were accompanied by other distinctive anatomic features that may tell us something about the process, or may be unrelated. By crossing these mice with another strain that does not show pathology, we will be able to determine what pathologic features are inherited together (thus caused by the same genes), how many genes are involved, and their approximate locations. Any gene(s) we find may have human counterparts that exert similar effects.

Research areas: auditory physiology/pathophysiology, cell biology of hearing and deafness

Long-term goal of research: Finding ‘risk’ genes may not point directly to cures or allow us to predict who will lose their hearing. Nevertheless, identifying the genes, gene networks, and gene products will help pinpoint key reactions that can be tweaked pharmacologically. We are among the first to seek out mouse strains with pathology of the stria vascularis and to use these to uncover genes that promote strial degeneration in mice, and possibly in humans.

Oregon Health & Science University
Changes in Residual Hearing in a Hearing-impaired Guinea Pig Model of Hybrid Cochlear Implants (CIs)

The goal of the current study is to understand mechanisms of hearing loss with “hybrid” or “electro-acoustic” cochlear implants (CIs), a new type of CI designed to preserve low-frequency hearing and allow combined acoustic-electric stimulation in the same ear. Hybrid CI users perform significantly better than standard CI users on musical melody recognition, voice recognition, and speech recognition in the presence of background talkers. However, approximately 10% of hybrid CI patients lose all residual hearing, and another 20% lose 20-30 dB after implantation. We hypothesize that in addition to surgical trauma, electrical stimulation through the hybrid CIs also damages cochlear cells, leading to the residual hearing loss (HL). Aim 1 is to determine the contribution of electrical stimulation to the residual HL in hybrid CI guinea pigs with noise-induced steeply-sloping high frequency hearing loss (NIHFHL). Aim 2 is to examine the effect of electrical stimulation on the cochlear pathology. The findings will guide the development of strategies to prevent hearing loss with electrical stimulation, and allow extension of the hybrid concept to all cochlear implant recipients with usable residual hearing.

Research area: Cochlear implants

Long term goal of research: To improve residual hearing preservation with “hybrid” or “electro-acoustic” cochlear implants (CIs), a new type of CI designed to preserve low-frequency hearing and allow combined acoustic-electric stimulation in the same ear.

Johns Hopkins University
Mechanisms involved in efferent synapse formation and maintenance in cochlear hair cells

This research aims at understanding the molecular mechanisms that underlie the formation and maintenance of the connections between the sensory hair cells and efferent nerve fibers that provide feedback from the brain to the ear. Such fibers are important modulators of inner ear activity. Our investigation includes different approaches (electrophysiology, confocal microscopy, and mouse genetics) in parallel.

Research area: synaptic transmission in the inner ear

Long-term goal of research: to understand the developmental machinery in the inner ear, which can lead to the ability to treat deficits in their function.

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.

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.