AHRF Researchers in the News

The American Hearing Research Foundation has selected five researchers to recieve one-year, $20,000 grants for 2007. The recipients, from universities around the nation, will investigate hearing and hearing disorders. Research ranges from studying how good and poor readers process sound, to genetics involved in the development of the cochlea.

Otoferlin’s Role in Hearing
Researcher to Investigate Reinnervation of Cochlear Hair Cells
Building an Ear From the Ground Up
Sound Processing and Reading: How Are They Related?
Protein May Hold Key to Hair Cell Regeneration

Otoferlin’s Role in Hearing

Neeliyath Ramakrishnan, Ph.D., of Wayne State University, Detroit, Michigan, will study the role of a protein called otoferlin and its function in hearing with the help of his 2007 grant from the American Hearing Research Foundation.

Mutations in the gene that codes for otoferlin can cause severe or total deafness. When this mutation is present, the only symptom is deafness, there are no other known consequences.

Otoferlin contains regions that bind calcium. These calcium-binding regions make otoferlin’s structure very similar to that of another protein, synaptotagmin I, known to support signaling between neurons by forming part of a specialized cellular structure (synaptic complex) that releases chemical neurotransmitter during communication between nerves. Synaptotagmin I, although widespread, is not present in the sensory cells of hearing (hair cells).

Sound triggers a rise in hair-cell calcium that is thought to be sensed by otoferlin, which in turn modulates and facilitates fusion of synaptic vesicles containing neurotransmitter, leading to transmitter release and ultimately, the perception of sound. Dr. Ramakrishnan and associates will examine whether otoferlin binds known proteins of the synaptic complex and/or unknown proteins that may also be involved in hearing. Dr. Ramakrishnan will also investigate whether otoferlin takes the place of synaptotagmin in hair cells, and if otoferlin’s structural similarities to synaptotagmin give clues as to the function of otoferlin in hearing and its malfunction in deafness.  

Additionally, the researchers will synthesize model proteins, in either normal or mutated form, so as to dissect their interactions at molecular level in the hair cell synaptic complex. Otoferlin, being a calcium sensor, may, for example, modulate the activity of voltage-gated calcium channels and proteins called SNAREs through direct protein-protein interactions. In this sense, otoferlin holds the key to synaptic transmission necessary for hearing.

Researcher to Investigate Reinnervation of Cochlear Hair Cells

Qiong Wang, M.D., Ph.D. of the University of Iowa, Iowa City is an AHRF grant recipient for 2007. Her research project, entitled “Reinnervation of Cochlear Inner Hair Cells by SGN Peripheral Processes in vitro,” will investigate how peripheral processes of neurons in the cochlea regenerate and reestablish functional connections with inner hair cells after noise-induced damage.

Synapses between hair cells and neurons in the cochlea are sensitive to sound vibrations entering the inner ear. Each hair cell is in contact with several neurons (called type I spiral ganglion neurons, or SGNs), which transmit the vibratory information to the brain, where it is interpreted as sound. Even brief exposure to noise can damage the terminal ends of SGNs (where they make contact with hair cells) and the synapses between SGNs and hair cells. The damage occurs when hair cells are overstimulated and release too much of a certain neurotransmitter, which causes the connection between the hair cells and the SGNs to break. When this happens, the SGN terminal ends shrink back, and some die off. The disconnection can lead to hearing loss. However, SGNs can regenerate and reestablish their connections with the inner hair cells. But researchers have found that the “system” does not return to absolute normal, although hearing is not immediately impaired. Exposure to excessive noise over time leads to accelerated hearing loss later in life. Dr. Wang will investigate what influences nerve regeneration after exposure to noise and how the reinnervation process may be lacking in some way. She especially interested in how the aberrant reinnervation could lead to accelerated hearing loss later in life.

Qiong Wang, MD. Ph.D, is a postdoctoral research scholar working in Dr. Steven Green’s lab in Department of Biological Sciences, University of Iowa in Iowa City. The AHRF has previously funded Dr. Green’s research.

Building an Ear From the Ground Up

Suzanne Mansour, Ph.D., an Associate Professor in the Department of Human Genetics at the University of Utah, Salt Lake City, received a grant from the AHRF for 2007 for her research project titled, “How to Build an Ear: Discovery of FGF-Regulated Hearing Loss Genes.”

To understand Dr. Mansour’s research, it is helpful to get an idea of how the ear forms during development.

The inner ear is a highly organized sensory organ with many specialized cell types that are responsible for both hearing and balance. Despite its complexity, all the cells that make up the inner ear are derived from a single patch of cells, referred to as the otic placode, which is located on the surface of the embryonic head. Small signaling molecules, termed Fibroblast Growth Factors (FGFs), function as molecular triggers to activate genes which specify what the cells will develop into, for example tissues of the ear, or other sensory organs or skin.

Dr. Suzanne Mansour and her colleagues at the University of Utah have shown that FGF3 and FGF10 are key regulators of ear development. Knock-out mice that lack both of these factors fail to initiate ear development of any kind, suggesting that these trigger molecules play critical roles at the top of a genetic hierarchy to activate a constellation of “inner ear-specific” genes.

The protein products of these genes, many of which have not yet been discovered, are ultimately responsible for building the specific components of the ear. Once these inner ear genes are activated by FGF3 and FGF10, their protein products transform the thin layer of embryonic cells into a sphere, which then continues to undergo complex reorganization to form the elaborate cochlear and vestibular structures (which are responsible for balance). FGFs are also required during these later stages of inner ear development to coordinate cellular proliferation, specialization and tissue movements. With these myriad roles, it is not surprising that several human hearing loss syndromes are caused by mutations affecting FGF signaling.

By comparing the genetic profile of mice lacking FGF3/10 with normal mice, Dr. Mansour plans to pinpoint the genes that are regulated by FGF3/10. In turn, the genes that are identified will be studied with various functional methodologies to uncover their specific role in ear development. These studies will ultimately contribute to our understanding of the genetic “blueprint” for ‘building an ear.’ Moreover, it is anticipated that many of these genes may be implicated in congenital hearing or balance disorders and that their discovery may suggest potential therapeutic interventions.

Sound Processing and Reading: How are They Related?

Catherine Warrier, Ph.D., of the Roxelyn and Richard Pepper Department of Communication Sciences and Disorders department at Northwestern University in Evanston, Illinois, is one of the recipients of an AHRF grant for 2007. Dr. Warrier will be using the grant to investigate the function of the auditory cortex (the part of the brain that interprets sounds from the ear) in good- and poor-reading children.

Learning disabilities are estimated to affect approximately eight percent of school-aged children in the United States. Further studies have found that many of these children have a hard time discriminating certain speech sounds, suggesting that an auditory deficit may underlie their learning disability.

Most normal brains have an asymmetrical distribution of white matter in the auditory cortex, with more white matter found on the left side. This increased white matter is believed to be due to increased myelination of the neurons. Myelin is an insulating substance that is found wrapped around neurons. Greater insulation allows for faster transmission of electrical impulses along the nerve fibers, aiding in rapid acoustic processing. Poor readers tend to have a more symmetrical processing of rapid sounds than normal reading children. It is believed that white matter in the auditory cortex of poor-reading children is more symmetrically distributed than in normal reading children.

Dr. Warrier wants to determine whether this anatomical asymmetry is related to the strength of asymmetric acoustical processing in normal- and poor-reading children. She will study 22 children aged 8 to 13 with normal hearing (11 normal readers and 11 poor readers). She hopes to understand the extent to which the structure of the auditory cortex influences how children process sounds, and learn how this relates to reading ability.

Protein May Hold Key to Hair Cell Regeneration

Tzy-Wen Gong, Ph.D., of the University of Michigan, will investigate the role of a newly-identified gene, UBE3B in the potential regeneration of hair cells in mammals.
Birds and reptiles have the ability to regenerate and regrow hair cells, an ability that mammals lack.

Dr. Gong and her team have determined that the protein UBE3B codes for, called ubiquitin ligase, is dramatically increased in the regions of the chick chochlea that are damaged by noise. Ubiquitin ligase is an enzyme that in turn, works to destroy other proteins.

Gong has determined that in chicks, after ubiquitin ligase is released, and its target proteins are destroyed, this process somehow triggers cells in the damaged region of the choclea to differentiate into new hair cells, thus replacing those that are lost as a result of noise trauma.

Little is known about this process, and Dr. Gong hopes to investigate how the degradation of specific proteins triggers cell differentiation into hair cells in chick cochlea. She hopes that her research may yield new insights into hair cell regeneration in mammals, and ultimately, humans.

At its 50th anniversary celebration held at Northwestern Memorial Hospital in Chicago on November 8, 2006, the American Hearing Research Foundation (AHRF) announced that there would be two recipients of the Birtman Grant, a one-year, $75,000 grant for research in hearing and balance disorders related to the inner ear.

“This grant is supposed to go to one lab per year,” says Richard G. Muench, Chairman of the Board of Directors of the AHRF, “but this year there were two truly outstanding proposals that we felt both merited the Birtman Grant.”

The recipients are Donna Whitlon, Ph.D., Associate Research Professor of Otolaryngology at Northwestern University Feinberg School of Medicine, who is  an expert on nerve fiber development and regeneration in the cochlea; and Timothy Hain, M.D., Professor of Neurology and Otolaryngology at Northwestern University Feinberg School of Medicine, Chicago, who is an expert on the treatment of patients with balance disorders. Both were on hand at the 50th anniversary celebration to get the news. Drs. Whitlon and Hain will each recruit a research fellow to work in their labs on their Birtman Grant research projects.

The Georgia Birtman Grant is made possible through the AHRF and Northwestern Memorial Foundation. It supports the advancement of research and education in otology and neurology at Northwestern Memorial Hospital and Northwestern University’s Feinberg School of Medicine. This annual $75,000 grant is named in honor of Georgia Birtman, a hearing impaired teacher who gave $2.1 million to the American Hearing Research Foundation in 1991. This year, two Birtman Grants were given.

“We were happy to see strong applications for the grants and to have the resources to fund two proposals through the Birtman Fund this year,” says Dennis Murphy, Executive Vice President and Chief Operating Officer of Northwestern Memorial Hospital. “The Fund promotes research into hearing and balance disorders, and both projects have the potential to significantly impact our knowledge of these disorders.”

Dr. Whitlon’s research focuses on the roles of chemical signaling in inducing the regrowth of neurons whose fibers are associated with hair cells. These neurons help transmit sound information from the hair cells in the cochlea to the brain. When hair cells are damaged or destroyed due to loud noises or ototoxic drugs, hearing loss results, and the neurons either die or undergo degeneration of their disconnected nerve fibers. Understanding the roles specific enzymes (called kinases) play in regenerating these neurons, can help lead to therapies aimed at inducing the regrowth of nerve fibers.

Dr. Whitlon and her team have already identified several signaling substances that seem to encourage neurite regrowth. Dr. Whitlon hopes that her research will suggest specific sites in the inner ear where pharmacological interventions may be applied that will stimulate nerve fiber growth. Her research is relevant to other research projects funded by the AHRF that aim to regenerate damaged hair cells, cells that will need to be reconnected to the brain stem by nerve fibers in order to reestablish hearing. In addition, this work has potential applications to the design of higher resolution cochlear implants.

Dr. Hain’s research focuses on modifications to the VEMP (Vestibular evoked myogenic potentials) test to make it more sensitive and accurate. VEMP tests assist in diagnosing dizziness disorders and can help to identify specific sites of injury to the inner ear, brain, neck and/or nerves associated with balance. During the non-invasive VEMP examination, small recording electrodes are taped to the neck of the patient. Sounds are presented to one ear while the patient’s neck muscles are contracted.

While VEMP testing is rapidly being adopted throughout the world, the nature of how the test is administered poses some problems. First, the electrical output recorded from the patient’s neck may be contaminated by other reflexes at work in the muscle during recording. Second, the test requires the patient to tense the neck muscles for the approximately 2 minutes it takes to administer the test, which can be difficult and tiring for some patients. By moving the electrodes to the triceps muscle of the arm, Dr. Hain hopes to improve the comfort of the patient as well as develop a method to diagnose cervical vertigo (vertigo due to neck injury). His research project involves investigating the accuracy and feasibility of VEMP testing at the triceps.