A5079604577- Hearing, Cochlea, Tinnitus, Genetics
- Hearing Loss and Rehabilitation
- Speech and Audio Processing
- Music and Audio Processing
- Biochemical Analysis and Sensing Techniques
- RNA and protein synthesis mechanisms
- RNA regulation and disease
- Marine animal studies overview
- Acoustic Wave Phenomena Research
- Vestibular and auditory disorders
- Congenital heart defects research
- Ion Channels and Receptors
- Ear Surgery and Otitis Media
- Immune Cell Function and Interaction
- MicroRNA in disease regulation
- Cancer-related molecular mechanisms research
- Connexins and lens biology
- Wnt/β-catenin signaling in development and cancer
- T-cell and B-cell Immunology
- Bioactive Compounds and Antitumor Agents
- Antimicrobial Peptides and Activities
- Genetic and Kidney Cyst Diseases
- Epigenetics and DNA Methylation
- Cytokine Signaling Pathways and Interactions
- Underwater Vehicles and Communication Systems
Massachusetts Eye and Ear Infirmary
2018-2025
Harvard University
2016-2025
Eaton (United States)
2023-2024
Lemuel Shattuck Hospital
2023
University of Kentucky
2011-2017
Howard Hughes Medical Institute
2015-2017
Adeno-associated virus (AAV) is a safe and effective vector for gene therapy retinal disorders. Gene hearing disorders not as advanced, in part because delivery to sensory hair cells of the inner ear inefficient. Although AAV transduces mouse cochlea, outer remain refractory transduction. Here, we demonstrate that vector, exosome-associated (exo-AAV), potent carrier transgenes all cells. Exo-AAV1-GFP more efficient than conventional AAV1-GFP, both cochlear explants vitro with direct...
Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new capsids must mediate efficient transgene expression both inner and outer cells the cochlea. Second, to have best chance translation, these also transduce non-human primates. Here, we show that an AAV9 capsid variant, PHP.B, produces a GFP reporter neonatal...
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...
Abstract The adult mammalian inner ear lacks the capacity to divide or regenerate. Damage generally leads permanent hearing loss in humans. Here, we present that reprogramming of induces renewed proliferation and regeneration cell types. Co-activation cycle activator Myc progenitor gene Notch1 robust diverse cochlear sensory epithelial Transient MYC NOTCH activities enable supporting cells respond transcription factor Atoh1 efficiently transdifferentiate into hair cell-like cells....
Mechanotransducer channels at the tips of sensory stereocilia inner ear hair cells are gated by tension 'tip links' interconnecting stereocilia. To ensure maximal sensitivity, tip links tensioned rest, resulting in a continuous influx Ca2+ into cell. Here, we show that this constitutive influx, usually considered as potentially deleterious for cells, is fact essential stability. In auditory young postnatal mice and rats, reduction mechanotransducer current, via pharmacological channel...
Abstract Usher syndrome type 1 F (USH1F), caused by mutations in the protocadherin-15 gene ( PCDH15 ), is characterized congenital deafness, lack of balance, and progressive blindness. In hair cells, receptor cells inner ear, a component tip links, fine filaments which pull open mechanosensory transduction channels. A simple addition therapy for USH1F challenging because coding sequence too large adeno-associated virus (AAV) vectors. We use rational, structure-based design to engineer...
The precise assembly of inner ear hair cell stereocilia into rows increasing height is critical for mechanotransduction and the sense hearing. Yet, how lengths actin-based are regulated remains poorly understood. Mutations molecular motor myosin 15 stunt growth cause deafness. We found that cells express two isoforms differ by inclusion an 133-kDa N-terminal domain, these can selectively traffic to different rows. Using isoform-specific knockout mouse, we show expressing only small isoform...
Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance hearing recovery patients with permanent loss. In mature mammalian cochlea, co-activation Myc Notch1 reprograms supporting cells (SC) promotes HC regeneration. Understanding the underlying mechanisms may aid development a clinically relevant approach achieve regeneration nontransgenic cochlea. By single-cell RNAseq, we show that MYC/NICD “rejuvenates” adult mouse cochlea by...
Abstract Our sense of hearing is mediated by cochlear hair cells, which there are two types organized in one row inner cells and three rows outer cells. Each cochlea contains 5–15 thousand terminally differentiated their survival essential for as they do not regenerate after insult. It often desirable research to quantify the number within samples, both pathological conditions, response treatment. Machine learning can be used automate quantification process but requires a vast diverse...
Abstract The bundle of stereocilia on inner ear hair cells responds to subnanometer deflections produced by sound or head movement. Stereocilia are interconnected a variety links and also carry an electron-dense surface coat. coat may contribute adhesion protect from fusion, but its molecular identity remains unknown. From database hair-cell-enriched translated proteins, we identify Polycystic Kidney Hepatic Disease 1-Like 1 (PKHD1L1), large, mostly extracellular protein 4249 amino acids...
Hair cells-the sensory cells of the vertebrate inner ear-bear at their apical surfaces a bundle actin-filled protrusions called stereocilia, which mediate cells' mechanosensitivity. Hereditary deafness is often associated with morphological disorganization stereocilia bundles, absence or mislocalization within specific proteins. Thus, bundles are closely examined to understand most animal models hereditary hearing loss. Because have diameter less than wavelength light, light microscopy not...
Abstract Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number individuals who remain without diagnosis after even most advanced genetic testing. PKHD1L1 was established as necessary for formation cochlear hair-cell stereociliary coat and causes in mice zebrafish when mutated. We sought to determine if biallelic variants also cause humans. Exome sequencing performed on DNA four families segregating autosomal recessive...
Hair cells of the inner ear are mechanoreceptors for hearing and balance, proteins highly enriched in hair may have specific roles development maintenance mechanotransduction apparatus. We identified XIRP2/mXinβ as an protein likely to be essential cells. found that different isoforms this expressed differentially located: short splice forms (also called XEPLIN) targeted more stereocilia, whereas two long containing a XIN-repeat domain both stereocilia cuticular plates. Mice lacking Xirp2...
Abstract Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via mechano-electrical transducer (MET) channels, composed TMC1/2 proteins. However, therapeutic use ototoxic drugs, such as aminoglycosides cisplatin, can enter cells through MET often leads profound auditory vestibular dysfunction. To date, our understanding how small-molecule modulators interact with TMCs remains...
Members of the TRP superfamily ion channels mediate mechanosensation in some organisms, and have been suggested as candidates for mechanotransduction channel vertebrate hair cells. Some can be ruled out based on lack an inner ear phenotype knockout animals or pore properties not similar to hair-cell channel. Such studies excluded Trpv4, Trpa1, Trpml3, Trpm1, Trpm3, Trpc1, Trpc3, Trpc5, Trpc6. However, others remain reasonable candidates. We used data from RNA-seq analysis gene expression...
Our sense of hearing is mediated by sensory hair cells, precisely arranged and highly specialized cells subdivided into outer (OHCs) inner (IHCs). Light microscopy tools allow for imaging auditory along the full length cochlea, often yielding more data than feasible to manually analyze. Currently, there are no widely applicable fast, unsupervised, unbiased, comprehensive image analysis that work well either with datasets containing an entire cochlea or smaller sampled regions. Here, we...
Excess noise damages sensory hair cells, resulting in loss of synaptic connections with auditory nerves and, some cases, hair-cell death. The cellular mechanisms underlying mechanically induced damage and subsequent repair are not completely understood. Hair cells neuromasts larval zebrafish structurally functionally comparable to mammalian but undergo robust regeneration following ototoxic damage. We therefore developed a model for this highly tractable system. Free swimming larvae exposed...
Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via mechano-electrical transducer (MET) channels, composed TMC1/2 proteins. However, therapeutic use ototoxic drugs, such as aminoglycosides cisplatin, can enter cells through MET often leads profound auditory vestibular dysfunction. Despite extensive research otoprotective compounds targeting our understanding how small...