MicroRNAs Involved in Aging of the Lateral Wall of the Cochlear Duct
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ABSTRACT: Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the cochlear duct (or scala media) in the inner ear are the two primary causes. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. We examined the change of miRNA gene expression profiles in the lateral wall of the cochlear duct in two mouse strains during aging
Project description:Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the cochlear duct (or scala media) in the inner ear are the two primary causes. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. We examined the change of miRNA gene expression profiles in the lateral wall of the cochlear duct in two mouse strains during aging The totoal RNA was extracted from the lateral wall of cochlear duct from CBA/J and C57BL/6J mice at different ages. The expression profile of miRNAs was examined by miR microarray GeneChip.
Project description:Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the scala media in the inner ear are the two primary causes. Transcriptome analysis has emerged as a powerful tool in revealing the genetic and molecular profile of a cell or a population of cells during aging in organism models, animals and humans. Comparison of transcriptomes between young and older animals have identified many common genes and pathways that are associated with aging and longevity. We used RNA-seq to examine changes in gene expression profiles of the stria vascularis between 9- and 26-month-old CBA mice. Our transcriptome analysis provides a rich resource for mechanistic studies of biological aging of stria vascularis.
Project description:A rat model of acute mitochondrial dysfunction in the cochlea is created by applying an irreversible mitochondrial complex II enzyme inhibitor, 3-NP, directly to the round window membrane. Treatment with 300 mM 3-NP results in temporary hearing loss (temporary threshold shift (TTS) model), whereas treatment with 500 mM 3-NP results in profound and permanent hearing loss (permanent threshold shift (PTS) model. Either treatment results with a primary histological change in the lateral wall spiral ligament. Because local ATP deprivation in the inner ear results from inhibition of inner ear mitochondrial function, this model replicates the etiology of inner ear energy failure caused by ATP deprivation due to inner ear ischemia. We used microarrays to detail the global programme of gene expression in the damaged cochlear lateral wall by 3NP and identified distinct classes of up-regulated/ down-regulated genes during the process. One and three day after administrated either 300 mM of 3-NP (TTS-1d and TTS-3d, respectably) or saline (Ctrl-1d and Ctrl-3d, respectably), rat cochear lateral wall in the apical side of the basal turn was harvested for RNA extraction and hybridization on Affymetrix microarrays.
Project description:Hearing loss is often due to the absence or the degeneration of hair cells in the cochlea. Understanding the mechanisms regulating the generation of hair cells may therefore lead to better treatments for hearing disorders. To elucidate the transcriptional control mechanisms specifying the progenitor cells (i.e. prosensory cells) that generate the hair cells and support cells critical for hearing function, we compared chromatin accessibility using ATAC-seq in sorted prosensory cells (Sox2-EGFP+) and surrounding cells (Sox2-EGFP-) from E12, E14.5 and E16 cochlear ducts. In Sox2-EGFP+, we find greater accessibility in and near genes restricted in expression to the prosensory region of the cochlear duct including Sox2, Isl1, Eya1 and Pou4f3. Furthermore, we find significant enrichment for the consensus binding sites of Sox2, Six1 and Gata3—transcription factors required for prosensory development—in the open chromatin regions. Over 2,200 regions displayed differential accessibility with developmental time in Sox2-EGFP+ cells, with most changes in the E12-14.5 window. Open chromatin regions detected in Sox2-EGFP+ cells map to over 48,000 orthologous regions in the human genome that include regions in genes linked to deafness. Our results reveal a dynamic landscape of open chromatin in prosensory cells with potential implications for cochlear development and disease.
Project description:This study investigates how lead exposure triggers cochlear synaptopathy and hearing loss in mice. Young-adult CBA/J mice were given lead acetate in drinking water for 28 days. We assessed hearing thresholds, outer hair cell activity, and synaptic changes in the cochlea. Lead exposure raises hearing thresholds, indicating cochlear synaptopathy. Notably affects synapses in the basal turn without impacting outer hair cells. In addition to this, lead altered the abundance of 352 synaptic proteins, with the synaptic vesicle cycle pathway prominently affected. Lead-induced cochlear synaptopathy targets basal cochlear regions, implicating synaptic vesicle cycle signaling in hearing loss. Revealing specific mechanisms behind lead-induced hearing deficits enhances targeted interventions and preventive strategies, advancing our understanding of lead induced hearing loss.
Project description:This study demonstrates the baseline data of gradient gene expression in the cochlea. Especially for genes whose mutations cause autosomal dominant non syndromic hearing loss (Pou4f3, Slc17a8, Tmc1, and Crym) as well as genes important for cochlear function (Emilin-2 and Tectb), gradual expression changes help to explain the various pathological conditions. Four C57BL/6 mice aged 6 weeks cochlea samples including the lateral wall, stria vascularis, spiral ligament, spiral prominence, and the organ of corti were dissected and separated into the apical, middle and basal turns to compare gene expression profiles of each cochlea turn.
Project description:A rat model of acute mitochondrial dysfunction in the cochlea is created by applying an irreversible mitochondrial complex II enzyme inhibitor, 3-NP, directly to the round window membrane. Treatment with 300 mM 3-NP results in temporary hearing loss (temporary threshold shift (TTS) model), whereas treatment with 500 mM 3-NP results in profound and permanent hearing loss (permanent threshold shift (PTS) model. Either treatment results with a primary histological change in the lateral wall spiral ligament. Because local ATP deprivation in the inner ear results from inhibition of inner ear mitochondrial function, this model replicates the etiology of inner ear energy failure caused by ATP deprivation due to inner ear ischemia. We used microarrays to detail the global programme of gene expression in the damaged cochlear lateral wall by 3NP and identified distinct classes of up-regulated/ down-regulated genes during the process.
Project description:Age-related hearing loss (ARHL) is a progressive sensorineural hearing loss that occurs as people get older. As many as 35% to 50% of the population aged between 65 and 75 have ARHL. Although age-related changes in the central auditory system can contribute to hearing impairment, degeneration of the mechanosensitive hair cells in the cochlea is the prevalent cause of ARHL. The molecular mechanisms of hair cell aging are largely unknown. To provide a comprehensive dataset of age-related genes and pathways in hair cells, we individually collected inner and outer hair cells, the two types of sensory receptor cells in the cochlea, from 9- and 26-month-old CBA/J mice and performed cell type-specific transcriptomic analysis. Our analysis showed a significant reduction of the expression of genes related to hair cell structure and function such as Tmc1, Kcnq4, Kcnj13, Slc7a14, Slc17a8, Chrna9/Chrna10, and Slc26a5. Our hair cell-specific transcriptome analysis provides a rich resource for mechanistic studies of biological aging of cochlear hair cells.
Project description:Age-related hearing loss (presbycusis) affects more than one-third of Americans over the age of 60, with its prevalence and severity increasing with age. Pathological alterations to the cochlear lateral wall (CLW) disrupting the maintenance of the endocochlear potential (EP) are a major cause of (metabolic) presbycusis. Although molecular mediators of CLW degeneration are largely unknown, several cellular events, including oxidative stress, apoptosis, and inhibition of proliferation, are known to contribute to this dysfunction. Here we have analyzed mRNA and microRNA expression in CLW of young and old mice to profile transcriptional changes that occur as a function of aging. Our results reinforce prior findings about molecular processes and pathways affected by aging and implicate microRNAs that may be involved in influencing these changes.