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Wu D.K.,National Institute on Deafness and Other Communication Disorders
Cold Spring Harbor perspectives in biology | Year: 2012

The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms.

Noben-Trauth K.,National Institute on Deafness and Other Communication Disorders
Advances in Experimental Medicine and Biology | Year: 2011

TRPML3 is a transient receptor potential (TRP) channel that is encoded by the mucolipin 3 gene (MCOLN3), a member of the small mucolipin gene family. Mcoln3 shows a broad expression pattern in embryonic and adult tissues that includes differentiated cells of skin and inner ear. Dominant mutant alleles of murine Mcoln3 cause embryonic lethality, pigmentation defects and deafness. The TRPML3 protein features a six-transmembrane topology and functions as a Ca 2+ permeable inward rectifying cation channel that is open at sub-physiological pH and closes as the extracytosolic pH becomes more acidic. TRPML3 localizes to the plasmamembrane and to early- and late-endosomes as well as lysosomes. Recent advances suggest that TRPML3 may regulate the acidification of early endosomes, hence playing a critical role in the endocytic pathway. © 2011 Springer Science+Business Media B.V.

Son E.J.,Yonsei University | Ma J.-H.,Yonsei University | Ankamreddy H.,Yonsei University | Shin J.-O.,Yonsei University | And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Sound frequency discrimination begins at the organ of Corti in mammals and the basilar papilla in birds. Both of these hearing organs are tonotopically organized such that sensory hair cells at the basal (proximal) end respond to high frequency sound, whereas their counterparts at the apex (distal) respond to low frequencies. Sonic hedgehog (Shh) secreted by the developing notochord and floor plate is required for cochlear formation in both species. In mice, the apical region of the developing cochlea, closer to the ventral midline source of Shh, requires higher levels of Shh signaling than the basal cochlea farther away from the midline. Here, gain-of-function experiments using Shh-soaked beads in ovo or a mouse model expressing constitutively activated Smoothened (transducer of Shh signaling) show up-regulation of apical genes in the basal cochlea, even though these regionally expressed genes are not necessarily conserved between the two species. In chicken, these altered gene expression patterns precede morphological and physiological changes in sensory hair cells that are typically associated with tonotopy such as the total number of stereocilia per hair cell and gene expression of an inward rectifier potassium channel, IRK1, which is a bona fide feature of apical hair cells in the basilar papilla. Furthermore, our results suggest that this conserved role of Shh in establishing cochlear tonotopy is initiated early in development by Shh emanating from the notochord and floor plate. © 2015, National Academy of Sciences. All rights reserved.

News Article
Site: www.biosciencetechnology.com

Some nerve cells in the inner ear can signal tissue damage in a way similar to pain-sensing nerve cells in the body, according to new research from Johns Hopkins. If the finding, discovered in rats, is confirmed in humans, it may lead to new insights into hyperacusis, an increased sensitivity to loud noises that can lead to severe and long-lasting ear pain. “We are still a long way from being able to treat hyperacusis,” said Paul Fuchs, Ph.D., professor of otolaryngology-head and neck surgery, neuroscience and biomedical engineering at the Johns Hopkins University School of Medicine, “but our results suggest that cells called type II afferent neurons are similar to pain-sensing neurons in the rest of the body, so lessons about interventions elsewhere could apply to the ear, too.” A summary of the research will be published online in the journal Proceedings of the National Academy of Sciences during the week of Nov. 9. The new discovery came as a result of interest in why this small subset of afferent nerve cells — nerves that take information from the inner ear to the brain — are quite insensitive to sound. “If they aren’t very good at relaying sounds, what are they doing?” said Fuchs. Fuchs and his team knew that these type II afferents connect to specialized sensory cells in the ear of mammals. These so-called outer hair cells amplify the sound waves that enter the inner ear, giving mammals very sensitive hearing over a wide range of frequencies. But, according to Fuchs, this specialization comes at a cost. “Outer hair cells are the canaries in the coal mine for the inner ear, in that they’re the first cells to die due to loud noise, age or other factors,” said Fuchs. “Since they can’t regenerate, their death leads to permanent hearing loss.” So one possible role for type II afferents, he adds, would be to warn the brain of impending damage to outer hair cells. It was known that nearby supporting cells respond to outer hair cell damage by increasing their inner calcium levels and releasing the chemical messenger ATP. Fuchs’ team knew that type II afferent neurons can respond to ATP, so they damaged outer hair cells while monitoring type II neurons in surgically removed inner ear tissue. Indeed, outer hair cell rupture caused robust excitation of type II neurons. Fuchs said that the ATP released by the supporting cells is probably what gets the neurons to fire, and the supporting cells might release ATP in response to ATP that leaks out of the ruptured outer hair cells. But he noted that “outer hair cells don’t have to rupture to release ATP. Progressive damage caused by loud noises or other stress is enough to increase ATP levels in the fluid of the inner ear.” Over evolutionary time, such a mechanism could have evolved to help mammals avoid further damage to their hearing. Such effects might depend on heightened sensitivity of the type II neurons after trauma, akin to the heightened sensitivity of pain-sensing nerves in damaged skin. Hypersensitivity to loud sound (hyperacusis) is a paradoxical consequence of hearing loss in many people. Everyday noises such as slamming doors, clanking dishes and barking dogs can become irritating and even painful. The good news, Fuchs said, is that the analogies with pain elsewhere in the body provide guidance for future studies. For example, a compound that suppresses pain-sensing nerve cells elsewhere, also prevented type II afferent neurons from firing in response to outer hair cell death. At present, Fuchs cautions, this is a restricted experimental result.  But, it provides a “proof of concept” for treating pain associated with inner ear damage. And the Fuchs laboratory plans to explore this question in their ongoing research. This work was supported by grants from the National Institute on Deafness and Other Communication Disorders.

Bainbridge K.E.,National Institute on Deafness and Other Communication Disorders | Hoffman H.J.,National Institute on Deafness and Other Communication Disorders | Cowie C.C.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases
Diabetes Care | Year: 2011

OBJECTIVE - The objective of this study was to examine the risk factors of low/mid-frequency and high-frequency hearing impairment among a nationally representative sample of diabetic adults. RESEARCH DESIGN AND METHODS - Data came from 536 participants, aged 20-69 years, with diagnosed or undiagnosed diabetes who completed audiometric testing during 1999-2004 in the National Health and Nutrition Examination Survey (NHANES). We defined hearing impairment as the pure-tone average >25 dB hearing level of pure-tone thresholds at low/mid-frequencies (500; 1,000; and 2,000 Hz) and high frequencies (3,000; 4,000; 6,000; and 8,000 Hz) and identified independent risk factors using logistic regression. RESULTS - Controlling for age, race/ethnicity, and marital status, odds ratios for associations with low/mid-frequency hearing impairment were 2.20 (95%CI 1.28-3.79) for HDL <40 mg/dL and 3.55 (1.57-8.03) for poor health. Controlling for age, race/ethnicity, sex, and income-to-poverty ratio, odds ratios for associations with high-frequency hearing impairment were 4.39 (1.26-15.26) for history of coronary heart disease and 4.42 (1.26-15.45) for peripheral neuropathy. CONCLUSIONS - Low HDL, coronary heart disease, peripheral neuropathy, and having poor health are potentially preventable correlates of hearing impairment for people with diabetes. Glycemic control, years since diagnosis, and type of glycemic medication were not associated with hearing impairment. © 2011 by the American Diabetes Association.

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