A5015203640- Cellular transport and secretion
- Cellular Mechanics and Interactions
- Hearing, Cochlea, Tinnitus, Genetics
- Lipid Membrane Structure and Behavior
- Cardiomyopathy and Myosin Studies
- Erythrocyte Function and Pathophysiology
- Muscle Physiology and Disorders
- Vestibular and auditory disorders
- 3D Printing in Biomedical Research
- Ion channel regulation and function
- Diet, Metabolism, and Disease
- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- Connexins and lens biology
- Liver Disease Diagnosis and Treatment
- Nanopore and Nanochannel Transport Studies
- Ocular Surface and Contact Lens
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- Distributed Sensor Networks and Detection Algorithms
- Advanced Fluorescence Microscopy Techniques
- Comparative Literary Analysis and Criticism
- Congenital heart defects research
- Genetic Neurodegenerative Diseases
- Biochemical Analysis and Sensing Techniques
University of Virginia
2022-2025
National Institutes of Health
2013-2024
Center for Cancer Research
2017-2024
National Cancer Institute
2017-2024
National Institute on Deafness and Other Communication Disorders
2013-2024
King's College London
2016
Queen Mary University of London
2009-2012
Mechanosensitive ion channels at stereocilia tips mediate mechanoelectrical transduction (MET) in inner ear sensory hair cells. Transmembrane channel-like 1 and 2 (TMC1 TMC2) are essential for MET hypothesized to be components of the complex, but evidence their predicted spatiotemporal localization is lacking. Here, we determine TMC proteins mice expressing TMC1-mCherry TMC2-AcGFP. Functionality tagged was verified by transgenic rescue currents hearing Tmc1(Δ/Δ);Tmc2(Δ/Δ) mice. TMC2-AcGFP...
Functional mechanoelectrical transduction (MET) channels of cochlear hair cells require the presence transmembrane channel-like protein isoforms TMC1 or TMC2. We show that TMCs are required for normal stereociliary bundle development and distinctively influence channel properties. TMC1-dependent have larger single-channel conductance in outer (OHCs) support a tonotopic apex-to-base gradient. Each MET complex exhibits multiple states ~50 pS increments, basal having more large-conductance...
Hair cells tightly control the dimensions of their stereocilia, which are actin-rich protrusions with graded heights that mediate mechanotransduction in inner ear. Two members myosin-III family, MYO3A and MYO3B, thought to regulate stereocilia length by transporting cargos actin polymerization at tips. We show eliminating espin-1 (ESPN-1), an isoform ESPN a cargo, dramatically alters slope staircase subset hair cells. Furthermore, we espin-like (ESPNL), primarily present developing is also...
Significance MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression posttranscriptionally. The evolutionarily conserved miR-183/96/182 cluster, consisting of three related miRNAs, is highly expressed in maturing sensory receptor cells. However, its role the functional maturation receptors has not been adequately addressed due to lack appropriate vivo models. We show deletion mice leads severe deficits vision, hearing, balance, and smell. These arise from defects timing...
Membrane remodeling plays a fundamental role during variety of biological events. However, the dynamics and molecular mechanisms regulating this process within cells in mammalian tissues situ remain largely unknown. In study, we use intravital subcellular microscopy live mice to study actomyosin cytoskeleton driving membranes large secretory granules, which are integrated into plasma membrane regulated exocytosis. We show that two isoforms nonmuscle myosin II, NMIIA NMIIB, control distinct...
WHRN (DFNB31) mutations cause diverse hearing disorders: profound deafness or variable loss in Usher syndrome type II. The known role of stereocilia elongation does not explain these different pathophysiologies. Using spontaneous and targeted Whrn mutants, we show that the major long (WHRN-L) short (WHRN-S) isoforms have distinct localizations within also across hair cell types. Lack both causes abnormally vestibular dysfunction. WHRN-S expression, however, is sufficient to maintain bundle...
Tuft cells are solitary chemosensory known for their distinct tall, blunt microvilli, thought to be analogous mechanosensory hair cell stereocilia. Identification of commonalities between tuft and could identify a role in mechanotransduction. Transcription factor POU2F3 is the master regulator formation, however how drives formation this unique functional microvillar apparatus unknown. ChIP-seq was performed on isolated compared cochlear transcriptome. Structural genes common both cells,...
Abstract The glycocalyx is a highly hydrated, glycoprotein-rich coat shrouding many eukaryotic and prokaryotic cells. intestinal epithelial glycocalyx, comprising glycosylated transmembrane mucins, part of the primary host-microbe interface essential for nutrient absorption. Its disruption has been implicated in numerous gastrointestinal diseases. Yet, due to challenges preserving visualizing its native organization, structure-function relationships remain unclear. Here, we characterize...
Lumen establishment and maintenance are fundamental for tubular organs physiological functions. Most of the studies investigating mechanisms regulating this process have been carried out in cell cultures or smaller organisms, whereas little has done mammalian model systems vivo. Here we used salivary glands live mice to examine role small GTPase Cdc42 regulation homeostasis intercellular canaliculi, a specialized apical domain acinar cells, where protein fluid secretion occur. Depletion...
Actin-based cellular protrusions are an ubiquitous feature of cells, performing a variety critical functions ranging from cell-cell communication to cell motility. The formation and maintenance these relies on the transport proteins via myosin motors, protrusion tip. While tip-directed motion leads accumulation motors (and their molecular cargo) at tip, it is observed that also form rearward moving, periodic isolated aggregates. origins mechanisms aggregates, whether they important for...
Membrane remodeling drives a broad spectrum of cellular functions, and it is regulated through mechanical forces exerted on the membrane by cytoplasmic complexes. Here, we investigate how actin filaments dynamically tune their structure to control active transfer membranes between compartments with distinct compositions biophysical properties. Using intravital subcellular microscopy in live rodents show that lattice composed linear stabilizes granule after fusion plasma network branched...
Microvilli-membrane bound actin protrusions on the surface of epithelial cells-are sites critical processes including absorption, secretion, and adhesion. Increasing evidence suggests microvilli are mechanosensitive, but underlying molecules mechanisms remain unknown. Here, we localize transmembrane channel-like proteins 4 5 (TMC4 5) calcium integrin binding protein 3 (CIB3) to microvillar tips in intestinal cells, near glycocalyx insertion sites. We find that TMC5 colocalizes with CIB3...
Within cells, vesicle fusion, scission, and the formation of intraluminal vesicles are critical processes that facilitate traffic, degradation, recycling cellular components, maintenance homeostasis. Despite significant advancements in elucidating molecular mechanisms drive these dynamic processes, direct situ visualization membrane remodeling intermediates remains challenging. Here, through application cryo-electron tomography mammalian we have identified a previously undescribed vesicular...
<title>Abstract</title> The complex, pleiomorphic membrane structure of the vesicular components within endolysosomal system has been appreciated through decades classical electron microscopy. However, due to heavy fixation and staining required in these approaches, situ visualization fragile intermediates between early endosomes, late endosomes ultimately multivesicular bodies (MVBs), remains elusive, raising likelihood that other structures may have also overlooked. Here, using...
Dry eye, characterized by symptoms of ocular discomfort and visual disturbances due to decreased tear secretion, affects 16 million Americans. Yet, there is currently no cure for dry eye as the mechanistic details water secretion in tear-producing lacrimal gland have not been fully elucidated. While a transcellular pathway via channels like AQP5 has reported, existence function paracellular tight junctions between epithelial cells remains controversial. The actomyosin cytoskeleton localizes...
Background and Aims: Intestinal epithelial barrier-integrity is essential for human health, its disruption induces exacerbates intestinal inflammatory disorders. While the cytoskeleton critical maintaining gut barrier-integrity, role of septins- newest family cytoskeletal proteins- unknown. To address this knowledge gap, we evaluate SEPT9- a component septin-cytoskeleton- in cell (IEC) barrier permeability inflammation. Methods: We developed SEPT9-NeonGreen knockin mice, inducible...
The mammary gland constitutes a model par excellence for investigating epithelial functions, including tissue remodeling, cell polarity, and secretory mechanisms. During pregnancy, the expands from primitive ductal tree embedded in fat pad to highly branched alveolar network primed formation secretion of colostrum milk. Post-partum, supplies all nutrients required neonatal survival, membrane-coated lipid droplets (LDs), proteins, carbohydrates, ions, water. Various milk components, lactose,...