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.

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.

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.

University of Kentucky
TRPA 1 activation in the cochlea as an intrinsic mechanism of protection against noise-induced hearing loss

TRPA1 is an ion channel mostly known for its role as an “irritant sensor” in pain-sensing neurons. Functional TRPA1 channels are also expressed in the inner ear. However, given that genetically modified mice lacking TRPA1 channels have typical hearing and balance, the role of these channels in the inner ear remains unknown. Noise exposure leads to the production of some of the cellular “irritants” that activate TRPA1 channels. Therefore, we hypothesized that TRPA1 channels are able to sense noise-induced damage in the cochlea. When we exposed adult mice to mild noise levels, we observed a temporary increase in hearing thresholds that lasted several days (making it harder to hear soft sounds). Mice lacking TRPA1 channels, however, recovered significantly faster than mice with typical TRPA1 expression. This project will explore whether, after noise exposure, TRPA1 activation contributes to the temporary shift in hearing thresholds to allow the cochlea enough time to repair or recover from the noise-induced tissue damage. This project will help us better understand the protective effects of TRPA1 activation after noise exposure, and the specific cell types within the inner ear that are involved in this process.

Johns Hopkins University
Investigating mechanisms of degeneration of ribbon synapses between auditory inner hair cells and type 1 afferent nerve fibers after noise trauma in mammals

Sensory hair cells in the inner ear pick up the sound signal and transmit it to auditory nerve fibers through chemical synapses by releasing the transmitter glutamate; auditory nerve fibers then transmit the sound-coding signal to the brain. Sound intensity is encoded by the amount of glutamate released by the hair cell, leading to glutamate receptor activation and then action potential firing in auditory nerve fibers. During noise exposure, auditory nerve fiber endings can be damaged short- or long-term, most likely due to an excessive influx of calcium. This phenomenon is called excitotoxicity, but the underlying mechanisms are not completely understood. This project will investigate molecular mechanisms of synaptic transmission between hair cells and auditory nerve fibers and how they are affected after noise trauma.

St. Jude Children's Research Hospital
Potential regeneration of auditory hair cells in the opossum, Monodelphis domestica

Millions of Americans suffer from sensorineural hearing loss: a disability that is permanent and on the rise as the iPod generation ages. For those who would seek to regain hearing, one potential solution may be offered by the regeneration of sensory hair cells within the inner ear. However, this is, as yet, unachievable in humans. Despite this, many non-mammalian vertebrates, like fish, amphibians, reptiles, and birds, naturally regenerate their sensory cells and regain their ability to hear, suggesting that humans lost this regenerative potential at some point during their evolution. It is hoped that discovering the critical differences between the hearing organs of these non-mammals and humans will allow us to manipulate the human ear to behave more like a bird’s or a reptile’s, and allow for human auditory cells to be regenerated. However, there are many differences between the ear of a human and that of a chicken, and narrowing down the search for the most important differences represents a daunting task. Marsupials, like the gray short-tailed opossum, represent an intermediate group, sharing many similarities with both humans and with non-mammals. Of particular interest, supporting cells in the opossum inner ear retain the ability to proliferate well after birth, an indication that these marsupials may possess some regenerative ability. This project aims to determine whether or not opossums are capable of hair cell regeneration or recovery of hearing and to characterize the extent of supporting cell proliferation that occurs both during development and after hearing loss. From this, comparisons will be able to be made between the various model species (e.g. chickens, opossums, humans) to gain a better understanding of which differences between the various hearing organs are essential for regeneration, and which differences are detrimental or unrelated.

Research area: hair cell regeneration

Long-term goal of research: The long term goal of the proposed research is to apply what we learn from proliferative and potentially regenerative processes in opossums and incorporate these discoveries into a comparative approach where we may discover key differences that either allow for regeneration to occur in the mammalian cochlea, or, conversely, prevent it. Once these differences are identified, we can begin to develop drugs and/or gene therapies for pre-clinical testing.

St. Jude Children's Research Hospital
Conditional Reprogramming of Otic Stem Cells: Development of a Novel In-Vitro Hair Cell Line

One of the major limitations in studies of hearing loss is the inability to study the phenomenon of hearing in a petri dish (in-vitro), thereby limiting the use of tools that are essential for understanding the causes of, and treatments for, hearing loss. In addition to this obvious limitation, the use of in-vitro studies is hindered primarily by technical limitations related to the low abundance of hair cells that are responsible for our sense of hearing. Researchers have attempted to overcome the issue of insufficient cell numbers by creating cell lines that mimic the properties of human hair cells, but success of these approaches have been limited. The goal of the proposed experiments is to utilize approaches from other fields to create a cell line that will allow for infinite proliferation of low abundance cells that can be turned into hair cells when needed, thus providing a limitless supply of hair cells for the study of hearing loss.

Research area: Hair Cells; Hearing Loss

Long-term goal of research: To identify drugs that can modulate the differentiation of hair cells, focusing primarily on compounds that promote hair cell formation, which we believe, will be of therapeutic benefit to people with hearing loss. To this end, we plan to utilize high throughput screening to test hundreds of thousands of compounds for potential effects on hair cell formation. We plan to combine the hair cell line that we create with various tools for tracking the developmental state of the cell to aid our evaluation of drugs that increase the number of all viable hair cells and to potentially extend our investigation to specific subtypes of hair cells that play distinct roles in hearing loss.

University of Michigan
Functions of supporting cell-derived neurotrophin-3 in noise-induced hearing loss

Emerging evidence shows that “benign” noise levels, initially thought to only result in temporary hearing impairment, can cause irreversible damage to the connections between hair cells the auditory neurons, and the synapses, which can lead to a permanent hearing decrease later in life. Currently, we have a limited understanding of how these synapses are maintained in the healthy cochlea and how they can be regenerated after noise overexposure. The overall goal of this study is to examine the potential of the neurotrophic factor, neurotrophin-3 (NT-3), to assist in preserving or regenerating these synaptic connections in cochlea after noise overexposure. We have generated genetic mouse models that allow us to remove or overproduce NT-3 from the supporting cells, which are the cells surrounding the sensory hair cells. We have found that NT-3 produced from the supporting cells is critical for regulation of hearing sensitivity and synaptic density in the cochlea. Based on this finding, we propose that NT-3 may present a novel therapeutic agent for NIHL. In this proposal, we will use these mouse models to address the following questions: does removing NT-3 exacerbate the damage to the loss of synapses and hearing sensitivity after noise overexposure? Does overproducing NT-3 prevent or promote recovery from noise-induced loss of synapses and hearing? These experiments will provide us with a better understanding of the pathophysiology of NIHL and the potential of neurotrophin-based therapeutics for treating hearing loss.