A5060312688- Hearing, Cochlea, Tinnitus, Genetics
- Vestibular and auditory disorders
- Hearing Loss and Rehabilitation
- Connexins and lens biology
- Plant Molecular Biology Research
- Barrier Structure and Function Studies
- Ear Surgery and Otitis Media
- Congenital heart defects research
- Muscle Physiology and Disorders
- Acoustic Wave Phenomena Research
- Ion Channels and Receptors
- Cancer-related molecular mechanisms research
- Cellular transport and secretion
- RNA and protein synthesis mechanisms
- Biochemical Analysis and Sensing Techniques
- Mitochondrial Function and Pathology
- Cell Adhesion Molecules Research
- Cardiomyopathy and Myosin Studies
- Microtubule and mitosis dynamics
- Ion channel regulation and function
- RNA regulation and disease
- RNA Research and Splicing
- ATP Synthase and ATPases Research
- interferon and immune responses
- RNA modifications and cancer
National Institute on Deafness and Other Communication Disorders
2015-2024
National Institutes of Health
2013-2024
Laboratory of Molecular Genetics
2006-2021
Stony Brook University
1999
Tight junctions (TJs) create ion-selective paracellular permeability barriers between extracellular compartments. In the organ of Corti inner ear, TJs reticular lamina separate K + -rich endolymph and Na perilymph. humans, mutations gene encoding claudin 14 TJ protein cause profound deafness but underlying pathogenesis is unknown. To explore role in ear other tissues we created a mouse model by targeted deletion Cldn14. allele lacZ cassette expressed under Cldn14 promoter. Cldn14-lacZ...
Sound and acceleration are detected by hair bundles, mechanosensory structures located at the apical pole of cells in inner ear. The different elements bundle, stereocilia a kinocilium, interconnected variety link types. One these links, tip link, connects top shorter stereocilium with lateral membrane an adjacent taller may gate mechanotransducer channel cell. Mass spectrometric Western blot analyses identify tip-link antigen, hitherto unidentified antigen specifically associated kinocilial...
Mutations of the gene encoding unconventional myosin XVa are associated with sensorineural deafness in humans (DFNB3) and shaker (Myo15sh2) mice. In deaf Myo15sh2/sh2 mice, stereocilia short, nearly equal length, lack immunoreactivity. We previously reported that mRNA protein expressed cochlear hair cells. now show mouse, rat, guinea pig, endogenous localizes to tips vestibular Myosin localization overlaps barbed ends actin filaments extends apical plasma membrane stereocilia. Gene...
Electromotility, i.e., the ability of cochlear outer hair cells (OHCs) to contract and elongate at acoustic frequencies, is presumed depend on voltage-driven conformational changes "motor" proteins present in OHC lateral plasma membrane. Recently, two membrane have been proposed as candidates for motor. A sugar transporter, GLUT-5, was based its localization OHCs observation that transport alters voltage sensitivity motor mechanism. Another candidate, "prestin," identified from a subtracted...
Deafness in spontaneously occurring mouse mutants is often associated with defects cochlea sensory hair cells, opening an avenue to systematically identify genes critical for cell structure and function. The classical semidominant mutant varitint-waddler (Va) exhibits early-onset hearing loss, vestibular defects, pigmentation abnormalities, perinatal lethality. A second allele, Va(J), which arose a cross segregating Va, shows less severe phenotype. By using positional cloning strategy, we...
The S1P(2) receptor is a member of family G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. widely expressed and linked to multiple protein signaling pathways, but its physiological function has remained elusive. Here we have demonstrated expression essential for proper functioning auditory vestibular systems. Auditory brainstem response analysis revealed receptor-null mice were deaf by one month age. These null...
Beta(cyto)-actin and gamma(cyto)-actin are ubiquitous proteins thought to be essential building blocks of the cytoskeleton in all non-muscle cells. Despite this widely held supposition, we show that null mice (Actg1(-/-)) viable. However, they suffer increased mortality progressive hearing loss during adulthood despite compensatory up-regulation beta(cyto)-actin. The surprising viability normal young Actg1(-/-) means beta(cyto)-actin can likely build actin-based cytoskeletal structures...
Dizziness and hearing loss are among the most common disabilities. Many forms of hereditary balance disorders caused by abnormal development stereocilia, mechanosensory organelles on apical surface hair cells in inner ear. The deaf whirler mouse, a model human Usher syndrome (manifested loss, dizziness, blindness), has recessive mutation whirlin gene, which renders cell stereocilia short dysfunctional. In this study, wild-type cDNA was delivered to ears neonatal mice using adeno-associated...
Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the link, with protocadherin 15 (PCDH15) at lower cadherin 23 (CDH23) upper end link. In terminally differentiated mammalian auditory cells, are subjected sound-induced forces throughout an organism's life. Although can regenerate disrupted restore hearing, molecular details this...
Hereditary deafness is one of the most common disabilities affecting newborns. Many forms hereditary are caused by morphological defects stereocilia bundles on apical surfaces inner ear hair cells, which responsible for sound detection. We explored effectiveness gene therapy in restoring cell architecture whirlin mouse model human deafness, deaf due to dysmorphic, short stereocilia. Wild-type cDNA was delivered via adeno-associated virus (AAV8) injection through round window cochleas...
Recessive mutations in myosin 15, a class XV unconventional myosin, cause profound congenital deafness humans and both vestibular dysfunction mice homozygous for the shaker 2 2J alleles. The allele is previously described missense mutation of highly conserved residue motor domain XV. lesion, contrast, 14.7 kb deletion that removes last six exons from 3"-terminus Myo15 transcript. These encode FERM (F, ezrin, radixin moesin) may interact with integral membrane proteins. Despite exons, mRNA...
Recessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindness syndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, segregating as recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total 23 these segregate USH1 due 17 homozygous mutant MYO7A alleles, which 14 are novel. One family segregated hearing loss DFNB2 novel three-nucleotide deletion an...