Inner ear immunity.

The inner ear, like all organs, interacts with the systemic immune system via lymphatic drainage and vascular circulation to protect itself from infections and stress such as acoustic trauma. The adult mammalian inner ear including the endolymphatic sac is populated with bone-marrow derived resident macrophages. Circulating macrophages continually renew the resident macrophage population.

Human Cytomegalovirus Interactions with the Basement Membrane Protein Nidogen 1.

In 2000, we reported that human cytomegalovirus (HCMV) induced specific damage on chromosome 1. The capacity of the virus to induce DNA breaks indicated potent interaction between viral proteins and these loci. We have fine mapped the 1q42 breaksite.

Pathology and mechanisms of cochlear aging.

Presbycusis, or age-related hearing loss (ARHL), occurs in most mammals with variations in the age of onset, rate of decline, and magnitude of degeneration in the central nervous system and inner ear. The affected cochlear structures include the stria vascularis and its vasculature, spiral ligament, sensory hair cells and auditory neurons. Dysfunction of the stria vascularis results in a reduced endocochlear potential.

Cellular mechanisms of noise-induced hearing loss.

Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory nerve output. Recent research has revealed a number of mechanisms that contribute to noise-induced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy.

Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited null mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei.

Effects of mitochondrial mutations on hearing and cochlear pathology with age.

Age-related hearing loss is a multi-factorial process involving genetic and environmental factors, including exposure to noise and ototoxic agents, as well as pathological processes. Among these is the accumulation of mitochondrial DNA mutations and deletions. The creation of a transgenic mouse with a loss-of-function deletion of the nuclear gene that encodes the polymerase required to repair damaged mitochondrial DNA (PolgA) enabled evaluation of age-related cochlear pathology associated with random mitochondrial DNA deletions that accrue over the lifespan of the mouse.

Dose-dependent sustained release of dexamethasone in inner ear cochlear fluids using a novel local delivery approach.

The thermo-reversible triblock copolymer poloxamer 407 was investigated as a drug delivery vehicle for micronized dexamethasone into the middle and inner ears of guinea pigs. The study characterized the gelation and in vitro release kinetics of poloxamer formulations. In vivo, the pharmacokinetic profile of formulations containing varying concentrations of poloxamer and dexamethasone was examined following intratympanic administration.

Acoustic trauma augments the cochlear immune response to antigen.

Objectives/hypothesis: To test whether noise-exposure, which activates a cochlear immune response with cytokine expression and infiltration of circulating leukocytes could augment the response to antigen (Ag).

Study Design: Randomized, prospective, mice.

Methods: We sensitized mice to an Ag, injected it intrathecally, and subsequently exposed the mice to noise (8-16 kHz, 90, 100, or 118 dB for 2 hours).

Tumor necrosis factor alpha can induce recruitment of inflammatory cells to the cochlea.

Hypothesis: Leukocyte recruitment to the cochlea can be induced by tumor necrosis factor alpha (TNF-alpha) at concentrations that are not cytotoxic to sensory cells in the organ of Corti.

Background: Leukocytes participating in inflammation enter the inner ear via the spiral modiolar vein and its tributaries. Many of the infiltrated leukocytes express TNF-alpha 3 hours after cochlear antigen challenge of systemically antigen-sensitized animals.

AM-111 reduces hearing loss in a guinea pig model of acute labyrinthitis.

Objectives/hypothesis: This study investigated the otoprotective properties of AM-111, an inhibitor of c-Jun N-terminal kinase-mediated apoptosis and inflammation.

Study Design: A controlled, prospective animal study using a guinea pig model of acute labyrinthitis.

Methods: Acute labyrinthitis was generated by injection of antigen into the scala tympani of sensitized guinea pigs.

A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.

Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects.

Immune cell recruitment following acoustic trauma.

Acoustic trauma induces cochlear inflammation. We hypothesized that chemokines are involved in the recruitment of leukocytes as part of a wound healing response. The cochleas of NIH-Swiss mice, exposed to octave-band noise (8-16 kHz, at 118 dB) for 2h, were examined after the termination of exposure.

Local perfusion of the tumor necrosis factor alpha blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss.

Objective: To evaluate the effect of transtympanic administration of tumor necrosis factor alpha (TNF-alpha) blockers to patients suffering from autoimmune inner ear disease (AIED).

Study Design: Nonrandomized, prospective pilot study.

Setting: Tertiary referral center.

Effects of antioxidants on the aging inner ear.

Age-related cochlear structural changes include the degeneration of sensory, neural cells and the stria vascularis. The hypothesis that cellular degeneration results from exposure to oxidative products of respiration was tested by supplementing aged dogs with a diet high in antioxidants and mitochondrial metabolites and by genetically modifying the expression level of the antioxidant, manganese superoxide dismutase (SOD2) in mice. Aged dogs received either a high antioxidant diet or a normal, control diet for the last 3 years of their life.

Transforming growth factor beta expression during an inner ear immune response.

Objectives: The involvement of transforming growth factor beta (TGF-beta), a strong mediator of fibrogenesis, during cochlear immune responses was investigated.

Methods: An inner ear adaptive immune response to antigen was created in mice that were painlessly sacrificed 3 to 48 hours and 7 days after initiation of the immune response. The cochleas were assayed by immunocytochemistry for TGF-beta and latency-associated peptide (LAP).

Cu/Zn superoxide dismutase and age-related hearing loss.

Mice, in which the genetics can be manipulated and the life span is relatively short, enable evaluation of the effects of specific gene expression on cochlear degeneration over time. Antioxidant enzymes such as Cu/Zn superoxide dismutase (SOD1) protect cells from toxic, reactive oxygen species and may be involved in age-related degeneration. The effects of SOD1 deletion and over-expression on the cochlea were examined in Sod1-null mice, Sod1 transgenic mice and in age- and genetics-matched controls.

Eya1 acts upstream of Tbx1, Neurogenin 1, NeuroD and the neurotrophins BDNF and NT-3 during inner ear development.

Cell fate specification during inner ear development is dependent upon regional gene expression within the otic vesicle. One of the earliest cell fate determination steps in this system is the specification of neural precursors, and regulators of this process include the Atonal-related basic helix-loop-helix genes, Ngn1 and NeuroD and the T-box gene, Tbx1. In this study we demonstrate that Eya1 signaling is critical to the normal expression patterns of Tbx1, Ngn1, and NeuroD in the developing mouse otocyst.

Cochlear microperfusion: experimental evaluation of a potential new therapy for severe hearing loss caused by inflammation.

Hypothesis: Cochlear microperfusion will be a useful treatment of severe sensorineural hearing loss caused by inflammation.

Background: Viruses, bacteria, and autoimmunity can initiate inflammation in the inner ear. The acute phase is associated with elevations in cytokines, nitrous oxide, and cellular infiltrates and the breakdown of the blood-labyrinthine barrier.

Innate immunity contributes to cochlear adaptive immune responses.

Inner ear immune responses mediated by antigen-specific processes are thought to contribute to hearing loss in humans. Systemic activation of innate immunity contributes to immune responses in the central nervous system. We hypothesized that activation of innate immunity can prime the inner ear for adaptive immune responses and exacerbate disease.

Age-related hearing loss and the ahl locus in mice.

C57BL/6 (B6) mice experience hearing loss and cochlear degeneration beginning about mid-life, whereas CAST/Ei (CAST) mice retain normal hearing until old age. A locus contributing to the hearing loss of B6 mice, named age-related hearing loss (ahl), was mapped to Chromosome 10. A homozygous, congenic strain of mice (B6.

A natural allele of Nxf1 suppresses retrovirus insertional mutations.

Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpn(vb) tremor mutation and the Eya1(BOR) model of human branchiootorenal syndrome.

Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation.

The inner ear is capable of rapidly mounting an immune response that can ultimately lead to cochlear degeneration and permanent hearing loss. The role of the endolymphatic sac in this immune process is not clear. In order to investigate the cytokine expression of cells within the endolymphatic sac, a secondary inner ear immune response to keyhole limpet hemocyanin (KLH) was created in mice.

Blockage of immune-mediated inner ear damage by etanercept.

Hypothesis: Etanercept will be able to reduce the inflammation and hearing loss associated with experimentally induced labyrinthitis.

Background: Inner ear immune responses cause hearing loss that may be reversible with pharmacologic treatment. Etanercept, tumor necrosis factor receptor blocker, was investigated in a guinea pig model of immune-mediated hearing loss.

Induction of MHC class II antigens on cells of the inner ear.

Growing evidence supports the concept that immune reactions occur in the cochlea, where they can function either in protection or as a source of inflammation. Since immunity is generally initiated by antigen presentation of foreign substances to T cells, antigen-presenting cells expressing major histocompatibility complex (MHC) class II molecules are required. Under resting conditions, cochlear cells usually express no MHC class II.