A5011657961- Hearing, Cochlea, Tinnitus, Genetics
- Hearing Loss and Rehabilitation
- RNA regulation and disease
- CRISPR and Genetic Engineering
- Polyomavirus and related diseases
- RNA and protein synthesis mechanisms
- Ear Surgery and Otitis Media
- RNA Interference and Gene Delivery
- Congenital heart defects research
- Nutrition, Genetics, and Disease
- Biochemical Analysis and Sensing Techniques
- Vestibular and auditory disorders
- Virus-based gene therapy research
- Acoustic Wave Phenomena Research
- Marine animal studies overview
- MicroRNA in disease regulation
- Cancer-related molecular mechanisms research
- Renal and related cancers
- Antimicrobial Peptides and Activities
- Epigenetics and DNA Methylation
- Nicotinic Acetylcholine Receptors Study
- melanin and skin pigmentation
- Viral Infections and Outbreaks Research
- Parvovirus B19 Infection Studies
- Developmental Biology and Gene Regulation
Harvard University
2011-2023
Massachusetts Eye and Ear Infirmary
2008-2023
Eaton (United States)
2023
Brigham and Women's Hospital
2014-2021
Nanjing Medical University
2020
Massachusetts General Hospital
2004-2008
University of Virginia
1999-2005
Molecular Oncology (United States)
2005
Howard Hughes Medical Institute
2005
Northwestern University
2005
In mammals, hair cell loss causes irreversible hearing and balance impairment because cells are terminally differentiated do not regenerate spontaneously. By profiling gene expression in developing mouse vestibular organs, we identified the retinoblastoma protein (pRb) as a candidate regulator of cycle exit cells. Differentiated functional with targeted deletion Rb1 undergo mitosis, divide, cycle, yet continue to become highly functional. Moreover, acute postnatal caused reentry....
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....
Abstract CRISPR/RfxCas13d (CasRx) editing system can specifically and precisely cleave single-strand RNAs, which is a promising treatment for various disorders by downregulation of related gene expression. Here, we tested this RNA-editing approach on Beethoven ( Bth ) mice, an animal model human DFNA36 due to point mutation in Tmc1 . We first screened 30 sgRNAs cell cultures found that CasRx with sgRNA3 reduced the transcript 90.8%, wild type + 44.3%. then injected newly developed AAV vector...
The retinoblastoma protein pRb is required for cell-cycle exit of embryonic mammalian hair cells but not their early differentiation. However, its role in postnatal unknown. To study the function mature animals, we created a new conditional mouse model, with Rb gene deleted primarily inner ear. Progeny survive up to 6 months. During development, −/− continue divide and can transduce mechanical stimuli. adult mice exhibit profound hearing loss due progressive degeneration organ Corti. We show...
Hearing loss, including genetic hearing is one of the most common forms sensory deficits in humans with limited options treatment. Adeno-associated virus (AAV)-mediated gene transfer has been shown to recover auditory functions effectively mouse models deafness when delivered at neonatal stages. However, cochlea still developing those time points, whereas humans, newborn inner ears are already fully mature. For effective therapy treat deafness, it necessary determine whether AAV-mediated can...
Myosin VI(MYO6) is an unconventional myosin that vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments Myo6 mutation causing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated vivo delivery Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate a Myo6WT/C442Y mouse model recapitulated phenotypes...
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...
Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is only treatment option. Poor outcomes are seen some patients. To develop biological for we generated a knockin mouse model frequent human DFNB8 mutation. The Tmprss3A306T/A306T homozygous mice display delayed onset progressive hearing loss similar to Using AAV2 as vector carry gene, AAV2-hTMPRSS3 injection adult inner ear results expression hair cells and...
Abstract The cell types of the inner ear originate from otic placode, a thickened layer ectoderm adjacent to developing hindbrain. placode invaginates and forms pit, which pinches off as small vesicle called otocyst . Presumptive cochleovestibular neurons delaminate anterior ventral part form ganglion ear. Here we show that LIM/homeodomain protein islet‐1 is expressed in cells this expression maintained at pit stages. Auditory vestibular islet‐1‐positive zone otocyst, these maintain until...
Isl1 is a LIM-homeodomain transcription factor that critical in the development and differentiation of multiple tissues. In mouse inner ear, expressed prosensory region otocyst, young hair cells supporting cells, no longer postnatal auditory cells. To evaluate how continuous expression affects cell cochlear function, we created transgenic model which Pou4f3 promoter drives overexpression specifically overexpressing develop normally, as seen by morphology functions (auditory brainstem...
Abstract LIM‐homeodomain transcription factors (LIM‐HDs) are essential in tissue patterning and differentiation. But their expression patterns the inner ear largely unknown. Here we report on a study of twelve LIM‐HDs, by tempo‐spatial that imply distinct yet overlapping roles, developing mouse ear. Expression Lmx1a Isl1 begins otocyst stage, with exclusively non‐sensory prosensory epithelia. The second wave at E12.5 includes Lhx3, 5, 9, Isl2 , Lmx1b differentiating sensory epithelia...
Retinoblastoma gene (Rb1) is required for proper cell cycle exit in the developing mouse inner ear and its deletion embryo leads to proliferation of sensory progenitor cells that differentiate into hair supporting cells. In a conditional Rb1 knockout mouse, Pou4f3-Cre-pRb(-/-), pRb(-/-) utricular survive adulthood whereas differentiation survival cochlear are impaired. To comprehensively survey pRb pathway mammalian ear, we performed microarray analysis (pRb(-/-) cochlea utricle. The...
Unlike mammals, the non-mammalian vertebrate inner ear can regenerate sensory cells, hair either spontaneously or through induction after cell loss, leading to hearing recovery. The mechanisms underlying regeneration are poorly understood. By microarray analysis on a chick model, we show that involves activation of proliferation genes and downregulation differentiation genes. Both MYC FGF activated in regeneration. Using zebrafish lateral line neuromast specific inhibition Myc Fgf suppresses...
Abstract Acetylcholine is a key neurotransmitter of the inner ear efferent system. In this study, we identify two novel nAChR subunits in ear: α1 and γ, encoded by Chrna1 Chrng , respectively. situ hybridization shows that messages these are present vestibular cochlear hair cells during early development. expression begin at embryonic stage E13.5 system E17.5 organ Corti. message continues through P7, whereas undetectable post‐natal P6. The γ known as muscle‐type surprisingly expressed which...
Highly immunogenic domains have not yet been defined in the extracellular protein of human immunodefiency virus type 2 (HIV-2) envelope. In this study, six contiguous segments covering entire HIV-2ST envelope were amplified and cloned into a bacterial expression vector to localize relative reactivity different regions molecule by Western blot (immunoblot) analysis. Our results demonstrate that HIV-2 contains highly epitopes with potential value as type-specific markers for infection.
The aim of this study was to an antimicrobial peptide (AMP), aurein 1.2, which substantially increased protein delivery directly into multiple mammalian inner-ear cell types in vivo. Different concentrations 1.2 with superpositively charged GFP (+36 GFP) fused Cre recombinase were delivered postnatal day 1-2 (P1-2) and adult cochleae reporter transgenic mice various methods. By cochleostomy at different 1.2–+36 (1 μM, 5 22.5 50 respectively), the tdTomato (tdT) expression observed outer hair...