A5071250155- Hearing, Cochlea, Tinnitus, Genetics
- Marine animal studies overview
- RNA Research and Splicing
- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- Biochemical Analysis and Sensing Techniques
- Cancer-related molecular mechanisms research
- RNA Interference and Gene Delivery
- Connexins and lens biology
- Cellular transport and secretion
- Underwater Vehicles and Communication Systems
- Congenital heart defects research
- Vestibular and auditory disorders
- Virus-based gene therapy research
- Erythrocyte Function and Pathophysiology
- Ion Channels and Receptors
- Head and Neck Surgical Oncology
- Cardiomyopathy and Myosin Studies
- Hearing Loss and Rehabilitation
- DNA and Nucleic Acid Chemistry
- Machine Learning in Bioinformatics
- RNA and protein synthesis mechanisms
- Biomedical Research and Pathophysiology
- Cardiovascular Effects of Exercise
- Ear Surgery and Otitis Media
Case Western Reserve University
2012-2023
University School
2010-2023
Freie Universität Berlin
2021
University Hospitals of Cleveland
2017-2019
University Hospitals Cleveland Medical Center
2015
Rockefeller University
2004-2010
Howard Hughes Medical Institute
2007-2010
Columbia University
2000-2003
National Institute of Arthritis and Musculoskeletal and Skin Diseases
2000
Harvard University
2000
Poliovirus initiates infection by binding to its cellular receptor (Pvr). We have studied this interaction using cryoelectron microscopy determine the structure, at 21-Å resolution, of poliovirus complexed with a soluble form (sPvr). This density map aided construction homology-based model sPvr and, in conjunction known crystal structure virus, allowed delineation site. The virion does not change significantly on short incubations 4°C. infer that configuration visualized represents initial...
Transient receptor potential (TRP) ion channels have been implicated in detecting chemical, thermal, and mechanical stimuli organisms ranging from mammals to Caenorhabditis elegans . It is well established that TRPA1 detects mediates behavioral responses chemical irritants. However, the role of thermal controversial. To further clarify functions vertebrates, we analyzed their roles zebrafish. The two zebrafish paralogs are expressed sensory neurons activated by several irritants vitro...
AbstractNectin-2 is a cell adhesion molecule encoded by member of the poliovirus receptor gene family. This family consists human, monkey, rat, and murine genes that are members immunoglobulin superfamily. Nectin-2 component cell-cell adherens junctions interacts with l-afadin, an F-actin-binding protein. Disruption both alleles nectin-2 resulted in morphologically aberrant spermatozoa defects nuclear cytoskeletal morphology mitochondrial localization. Homozygous null males sterile, while...
Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)–dependent control of remodeling at the midbody, subcellular organelle defines cleavage site. Alteration function can lead to cataract, but underlying mechanism its relation cytokinesis are unclear. We found lens-specific cytokinetic PI3K-C2α (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α), lipid product PI(3,4)P
Detection of water motion by the lateral line relies on mechanotransduction complexes at stereocilia tips. This sensory system is comprised neuromasts, patches hair cells with stereociliary bundles arranged morphological mirror symmetry that are mechanically responsive to two opposing directions. Here, we find transmembrane channel-like 2b (Tmc2b) differentially required for in zebrafish line. Despite similarities neuromast cell morphology, three classes these can be distinguished their...
Usher syndrome type III (USH3) is characterized by progressive loss of hearing and vision, varying degrees vestibular dysfunction. It caused mutations that affect the human clarin-1 protein (hCLRN1), a member tetraspanin family. The missense mutation <i>CLRN1<sup>N48K</sup></i>, which affects conserved <i>N</i>-glycosylation site in hCLRN1, common causative USH3 among Ashkenazi Jews. affected individuals hear at birth but lose function over time. Here, we developed an animal model system...
ABSTRACT We examined the role of soluble poliovirus receptor on transition native (160S or N particle) to an infectious intermediate (135S A particle). The viral behaves as a classic state theory catalyst, facilitating N-to-A conversion by lowering activation energy for process 50 kcal/mol. In contrast earlier studies which demonstrated that capsid-binding drugs inhibit thermally mediated through entropic stabilization alone, are shown receptor-mediated combination enthalpic and effects.
An understanding of the molecular bases morphogenesis, organization, and functioning hair cells requires that genes expressed in these be identified their functions ascertained. After purifying zebrafish detecting mRNAs with oligonucleotide microarrays, we developed a subtractive strategy 1,037 cell-expressed whose cognate proteins subserve including membrane transport, synaptic transmission, transcriptional control, cellular adhesion signal transduction, cytoskeletal organization. To assess...
To study the kinetics and equilibrium of poliovirus binding to receptor, we used surface plasmon resonance examine interaction a soluble form receptor with poliovirus. Soluble purified from mammalian cells is able bind poliovirus, neutralize viral infectivity, induce structural changes in virus particle. Binding studies revealed that there are two sites for on type 1 capsid, affinity constants at 20 °C <i>K</i><sub>D</sub><sub>1</sub> = 0.67 μm <i>K</i><sub>D</sub><sub>2</sub> 0.11 μm. The...
The precise morphology of the mechanosensitive hair bundle requires seamless integration actin and microtubule networks. Here, we identify Acf7a (actin crosslinking family protein 7a) as a positioned to bridge these distinct cytoskeletal networks in cells. By imaging Acf7a–Citrine fusion zebrafish immunolabeling vestibular cochlear mouse cells, show that ACF7 circumscribe, underlie, are interwoven into cuticular plate (CP), they also encircle basal body kinocilium. In localization is graded,...
Stereocilia are actin-filled protrusions that permit mechanotransduction in the internal ear. To identify proteins organize cytoskeleton of stereocilia, we scrutinized hair-cell transcriptome zebrafish. One promising candidate encodes fascin 2b, a filamentous actin-bundling protein found retinal photoreceptors. Immunolabeling zebrafish hair cells and use transgenic expressed 2b fused to green fluorescent demonstrated localized stereocilia specifically. When actin recombinant fusion...
Permanency of mechanosensory stereocilia may be the consequence low protein turnover or rapid renewal. Here, we devise a system, using optical techniques in live zebrafish, to distinguish between these mechanisms. We demonstrate that stereocilium's abundant actin cross-linker fascin 2b exchanges, without bias phosphointermediate, orders magnitude faster (t1/2 76.3 s) than any other known hair bundle protein. To establish logic 2b's exchange, examine whether filamentous is dynamic and detect...
Cisplatin and other related platinum antineoplastic drugs are commonly used in the treatment of a variety cancers both adults children but often associated with severe side effects, including hearing loss. Cisplatin's ototoxic effects multifaceted, culminating irreversible damage to mechanosensory hair cells inner ear. Platinum act on cancerous by forming nuclear DNA adducts, which may initiate signaling leading cell cycle arrest or apoptosis. Moreover, it was reported that cisplatin induce...
Abstract Perception of sound is initiated by mechanically gated ion channels at the tips stereocilia. Mature mammalian auditory hair cells require transmembrane channel-like 1 (TMC1) for mechanotransduction, and mutations cognate genetic sequences result in dominant or recessive heritable deafness forms humans mice. In contrast, zebrafish lateral line cells, which detect water motion, Tmc2a Tmc2b. Here, we use standard multiplex genome editing conjunction with functional behavioral assays to...
Hair cells are heterogenous, enabling varied roles in sensory systems. An emerging hypothesis is that the transmembrane channel-like (Tmc) proteins of hair cell’s mechanotransduction apparatus vary within and between organs to permit encoding different mechanical stimuli. Five anatomical variables may coincide with Tmc use by a cell ear containing organ, morphology, position an axis best sensitivity for cell, bundle’s orientation this axis. Here, we test zebrafish using suite genetic...
Key points The synaptic ribbon is an organelle that coordinates rapid and sustained vesicle release to enable hearing balance. Ribeye a b proteins are major constituents of the in hair cells. In this study, we use optically clear transgenic zebrafish examine potential dynamics ribeye vivo . We demonstrate inherently dynamic but stabilized at ribbons cells ear lateral line system. Abstract protein constituent ribbon, considered be stable structure. However, under certain physiological...
Significance We report on a zebrafish model of hearing loss in Usher syndrome type IIIA caused by pathogenic variant c.144T>G (p.N48K) the clarin1 gene ( CLRN1 ). expressed wild-type or knockout and then probed these animals with genetic pharmaceutical small-molecular agents. Our findings revealed that N48K protein is transported to hair cell bundle via an unconventional secretory pathway, activation this pathway using artemisinin, antimalarial drug, enhanced levels bundles rescued their...
Hearing impairment (HI) is a common disorder of sensorineural function with highly heterogeneous genetic background. Although substantial progress has been made in the understanding etiology hereditary HI, many genes implicated HI remain undiscovered. Via exome and Sanger sequencing DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual we identified rare homozygous missense variants four (ADAMTS1, MPDZ, MVD, SEZ6) are likely underlying cause HI....